8/23/2019 Lecure 2 Learning Objectives
● Begin identifying the basic structures of the human brain
● Describe the different planes of section
● Name two uses for fluorescence microscopy
○ Fluorescence- a property of some atoms and molecules that enables them to
absorb a certain wavelength and then emit light of a longer wavelength
○ Confocal flurescence - shile light at a tissue and measures what comes back.
Focus excitation photons, and depending on objective, can hit different layers of
the tissue, thus give off different photos and this is collected. Has to go through
special cameras. More detail!
● Name two uses for model organisms
● Describe the basic methods of MRI, PET, and fMRI and their uses
○ Magnetic resonance imaging (MRI) - structural analysis. To visualisze disease,
and injury. Great when combined with CT scan. Look at VBR (ventricle to brain
ratio). Use blood flow as a proxy for brain acitivity.
○ Positron emission tomography (PET) - use blood flow as a proxy for brain
activity. Can make use of tracer substances that get absorbed by some tissues.
Drug binding, drug specificity, and receptors.
○ Single-photon emission computerized tomography (SPECT) ● Explain how analysis at various levels of brain organization may help
● understand brain function and disease
8/25/2019 Learning Objectives
● Begin identifying the basic structures of the human brain
○ See colorings
● Describe the different planes of section
○ Sagittal plane -cut the corpus callosum and where the longitudinal fissure are
○ horizontal plane - cut like a hamburger (h and h)
○ Frontal plane- like slice bread (cause we f**ing love sliced bread)
● Name two uses for fluorescence microscopy
○ Fluorescence - a property of some atoms and molecules that enables them to
absorb a certain wavelength and then emit light of a longer wavelength.
○ Electrons can be excited to a higher energy state, and when they return, they
sometimes give off energy in the form of light.
○ Fluorescence is the is immediate emissions of absorbed radiation
○ Confocal fluorescence microscopy has striking advantages over conventional
fluorescence microscopy
○ Uses
■ shine a light as a tissue and measures what comes back
■ Can add fluorescent dyes that indicatie Ca ions in the brain, especially if
the slices are taken from genetically engineered animals
● Brighter colors, higher levels of calcium. This indicated dynamics
going on/what cells are active more neuronal activity
● Higher levels, more Ca, more blue and vice versa
● Name two uses for model organisms
○
●
Some animal models allow for imaging of the whole brain at the single cell
resolution during behavior - can correlate behavior with neuronal activity (Circle
at top gets bigger when calcium gets bigger in video
■ You wouldn’t know which connection is important for which behavior
without the pathways and what not.
○ Can genetically engineer animals so that each neuron can be fluored in a
different colors - gives us the fine details of many neurons simultaneously
○ Can focus on an animal with a specialization (ex. Squid with long axons) and
once have a good understanding, can generalize to other animal/look at other
animals.
Describe the basic methods of MRI, PET, and fMRI and their uses
○ MRI - magnetic resonance imaging:
■ Good for resting brain, very expensive, non invasive
■ Use blood flow as a proxy for brain activity
■ Method: water molecules align in a strong magnetic field. Mesures
relaxation of movement of water molecules.
● Blood oxygen level dependent imaging
○ Hemoglobin with/without oxygen move differently in a
magnetic field.
■ Close eyes and let blood vessels relax / open eyes
and wait for blood vessels to dilate (blood come to
them aka vascularize)
■ Dead neurons don’t vascularized, tumors have low
vascularization, then super high once start getting
blow flow.
● MRI allows us to visualize
○ disease. Ex. enlarged ventricles are common in some
patients with schizophrenia. (large ventricles are seen post
cell death)
○ Injury - TBI,
■ Hemosiderin- inclusions of iron, often seen after
bleeding (haemorrhage)
● Diffusion tensor imaging of water - can differentiate the mobility
of water within neuronal processes (axons mostly) from water
molecules in the interstitial fluid. H2) in axons is less mobile so the
molecules signal differently.
○ show predominantly axon tracts.
○ PET- positron emission tomography :
■ Good for resting brain, very expensive
■ Use blood flow as a proxy for brain activity
■ Method : makes use of tracer substances that get absorbed by some
tissues.
● Ex. FDG (fluorodeoxyglucose) : blood cells take it up but cannot
digest it so FDG becomes trapped in metabolically active neurons
●
○ Did with worms
Imaging reception activity in the presence of drugs show WHERE
the drugs are acting - ex evaluation of antipsychotic drugs by PET
imaging
○ Image receptor localization
○ My dog ate my food (FDG) WHERE did he go/ where is he
active
○
○
○
SPECT- single photon emission computerized tomography :
CT - computerized axial tomography : essentially multiple x rays of the brain
taken at different angles and combining them with an MRI
■ Day of brain injury shows brain swelling indicated by ventricle to brain
ratio (vbr)
■ Cheaper and faster than a MRI
●
Explain how analysis at various levels of brain organization may help
○ Neuronal connection can be visualized with labels that get transported across or
taken up at synapses.
■ Each individual neuronal connection is not important for every single
behavior the particular neuron is involved with. But you would know the
important ones with the pathways and what not.
■ Think human genome project but with neurons
○ This knowledge can be useful to disrupt or strengthen pathways
○ Anterograde: soma to synapse
○ Retrograde: soma to synapse (retrograde engineering)
● understand brain function and disease
○ MRI : Dead neurons don’t vascularized thus black (???)
○ MRI : Tumor will have low vascularization, the crazy high vascularization as it
steals blood sources, thus will later appear bright white (??)
○ CT Scan : Severe traumatic brain injury (TBI) - day of injury increase VBR
(ventricle to brain ratio) aka swelling. Later, ventricles are enlarged, degeneration
is observes, normal VBR.
○
8/27/2019 Learning Objectives
● Describe the basic methods of MRI, PET, and fMRI and their uses
○ Overall
■ Advantages
● Useful for normal, disease, resing, active brain
● Can detect glucose, blood flow, and few molecules, and
broad/slow activity
■ Disadvantages
● Expensive
● Uncomfortable to lie still on table, slow scans
● Some medications may interfere with accuracy of results (high
blood glucose levels in diabetes)
■ Blood flow as a proxy for brain activity
● Neurons and glial cells use energy/ ATP when active, mostly
replenished by oxidative metabolism, blood vessels near active
cells dilate to keep up with the demands.
■ Uses - IN MI (in me)
● Information processing
● Neurodevelopment
● Mental illness
● injury
○ MRI - measures how fast/slow water molecules with relax from high excitation
states
■ Flips a spinning electron 90*, and we measure (via antenna) how long it
takes the electron to flip back
○ PET - detects tracer substances that get absorbed by some tissues
■
■
●
●
●
Drug binding, drug specificity, and receptory
Imagine receptor activity in the presence of drugs show WHERE drugs
are acting
● ex DOPA a precursor to dopamine
Explain how analysis at various levels of brain organization may help
○ Brain everything depends on sex, size, age, etc
■ Used to base all brains off the talairach atlas from 1 women
■ Landmarks are now posterior commissure and anterior commissure
○ understand brain function and disease
Name the major subdivisions of the human nervous system
○ CNS Central nervous system = brain + spinal cord
○ ENS Enteric (gut) nervous system - autonomic neurons that innervate stomach
and intestine
○ PNS peripheral nervous system - any nerves or neurons outside of the brain and
spinal cord
Name and ascribe functions to major regions of the cortex, cerebellum, and brainstem
○ Cortex
■ Frontal lobe - motor, higher order cognitive/associative (integrate multiple
senses or sensory/motor)
● Primary motor cortex (separated via central sulcus)
● Broca’s area - speech production
● Frontal eye field - directs eye movement (motor side of it)
○ Where: intersection of the middle frontal gyrus with the
precentral gyrus
■ Parietal lobe - somatosensory (touch), associative
● Primary somatosensory cortex (separated via central sulcus)
● Parietal is on top of temporal (goes alphabetical top to bottom, P
comes before T)
■ Occipital lobe - vision, associative
■ Temporal lobe - auditory, associative
● Wernicke’s area - language comprehension
■ Corpus callosum - large bundle of axons that connect left/right
hemispheres
■
Cerebellum
■ part of feedback loop regulating movement, balance
○ Brainstem
■ Pons and medulla
Name and describe the major blood vessels supplying cortex
○ Anterior brain
■ Anterior cerebral artery (the hair)
■ Internal carotid artery (ears going in)
■ Middle cerebral artery (ears going out)
○ Posterior brain
■ Vertebral (legs)
○ Circle of Willis
■ Anterior communicating (between antenna)
■ Anterior cerebral (forehead side)
■ Posterior communicating (cheek side)
○ Posterior cerebral artery (upper arm)
Name some of the major sulci and gyri of the cortex
○ Central sulcus separates precentral/postcentral gyrus (motor and somatosensory
cortex)
○ See drawn study guide
Describe the cellular differences and connections that distinguish major cortical areas
○
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●
Lecture 4
● Name some of the major sulci and gyri of the cortex
○ Central Sulcus (separates frontal and parietal lobes) & Lateral Sulcus (separates
temporal lobes)
■ Central seperate precentral gyrus (motor cortex) from post central gyrus
(somatosensory cortex) M comes before S alphabetically (so motor
before somatosensory cortex split by central sulcus)
○ Parietal lobe
■ Superital lobule
■ Intraparietal sulcus
●
●
■ Inferior parietal lobule
○ Temporal lobe
■ Superior temporal gyrus
■ Middle temporal gyrus
■ Inferior temporal gyrus
○ Frontal lobe
■ Superior frontal gyrus
■ Middle frontal gyrus
■ Inferior gyrus
■ Below -> orbital cortex
○ Where is cingulate gyrus, PHH, OTG?
Describe the cellular differences and connections that distinguish major cortical areas
○ As always form fits function :) … the neurons and connections of cortex define
its function
■ Pyramidal cells- are the output cells of the cortex. They project to other
cortical areas (thalamus, cerebellum, and spinal cord). Are glutamatergic
(excitatory)
● *Thalamus: gateway to cortex
■ Stellate Cells- input cells of the cortex. They project locally. Can be
glutamatergic/GABAergic (inhibitory)
■ https://youtu.be/4DOBEbJwm9c
List 4 different subcortical structures, describe their location,and provide a basic
description of their functions
○ Subcortical structures are a group of diverse neural formations within the brain
which include the…..(below).... Include functions like memory, emotion, pleasure,
hormone production and act as information hubs of the nervous system
○ Diencephalon
■ Where: posterior part of the forebrain deep within the cerebrum
■ Function:
■ Pieces
● Thalamus - Relay center between brainstem and cellebrum.
Relaying sensory and motor signals and regulating
consciousness, sleep, and alertness. Is a gateway that regulates
information to and from cortex. Contains…
○ Mediodorsal nucleus
○ Medial Geniculate Body
○ Lateral Geniculate Body
○ Pulvinar
○ VPL
○ VL
○ VA
● Epithalamus - Contains the pineal gland (sleep wake
cycle/circadian rhythm via melatonin) and initiation/control of
movements
●
●
○
○
○
Subthalamus- Control of motor activity and accuracy of body
movements. Controlling sexual behavior.
Hypothalamus - Maintains endocrine and autonomic functions.
Controlling mechanism related to survival such as food and fluid
intake, sleeping, metabolism, and body temp, enables a state of
homeostasis. Can help mediate the stress response, metabolism
intensite, reproduction.
Pituitary gland
■ Where: Sella turcica of the sphenoid bone
■ Function: Major gland of the human body. Stores thyroid stimulating
hormone, oxytocin, and vasopressin.
Limbic structures
■ Where:
■ Function: Relay center between brainstem and cerebrum. General term
used to describe the structures that control emotions (fear, pleasure,
anger) and drives (hunger, sex, care of offspring)
■ Pieces
● Hippocampus - memory storage and spatial navigation. Spatial
memory. (within temporal lobe)
● Mammillary bodies - simply an extension of the hypothalamus
● Amygdala - fear processing and fear related memory (within
temporal lobe)
● Fornix - a white matter axon tract that serves as the output of the
hippocampus. Output of hippocampus
● Septal nuclei - connections to the olfactory bulb, hippocampus,
amygdala, hypothalamic nuclei, midbrain, habenular nuclei,
cingulate gyrus, and thalamus. The pleasure sensations.
● Stria terminalis- output of amygdala, connections to habenular,
and mammillary (hypothalamic) nuclei. Output of amygdala to
hippocampus. How amygdala communicates to thalamus to
release cortisol adrenal gland (on top of kidney) for fight or flight.
● Cingulate gyrus/ Cingulate cortex - pain and visceral responses
● Parahippocampal gyrus
● Medial orbitofrontal gyri
● Temporal poles
● Anterior part of insular cortex
● Olfactory cortex
● Diencephalon
● Basal ganglia
● Basal forebrain
● Septal nuclei
● brainstem
Basal ganglia
■ Where: Anterior to primary motor cortex
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■
■
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Function: Group of interconnected grey matter. Help in fine tuning motor
function. Send signals to the thalamus that determine how the thalamus
will affect the motor cortex. *involuntary hand shaking-tremor- Parkinson’s
disease*
Function: interconnected nuclei between the cingulate cortex, thalamus,
hypothalamus, and hippocampus (in the center of the brain). Part of a
feedback loop that regulates behavior selection (what is appropriate, what
will lead us to a goal, etc)
Pieces
● Caudate nucleus - head, body, tail
● Putamen
● Globus pallidus - internal/externa;
● Substantia nigra
● Subthalamic nucleus
●
○ https://www.kenhub.com/en/library/anatomy/subcortical-structures-anatomy
List the cranial nerves along with the targets they innervate
○ Optic Nerve - eyes
○ Olfactory nerve - nose
○ Oculomotor nerve - ciliary muscle, sphincter of pupil and all external eye muscles
except the superior oblique and lateral rectus
○ Trochlear nerve - superior oblique muscle
○ Trigeminal nerve - sensory, face sinuses, teeth (ophthalmic, maxillary,
mandibular)
○ Abducens - lateral rectus muscle
○ Facial nerve - muscles of the face
○ Vestibulocochlear - cochlear and vestibular (ear)
○ Glossopharyngeal nerve - sensory- posterior ⅓ of the tongue, tonsils, pharynx,
middle eary. Motor- stylopharyngeus, upper pharyngeal muscles, parotid gland,
○ Vagus nerve - Motor - heart, lungs, palate, pharynx, larynx, trachea, bronchi, GI
tract. Sensory - heart, lungs, trachea, bronchi, larynx, pharynx, GI tract
○ Accessory nerve - sternocleidomastoid, trapezius muscles
○ Hypoglossal nerve - tongue muscles, strap muscles by ansa
Explain the organization of the spinal cord segments related to sensory innervation and
motor output
○ below
●
Stuff I think it important and worth knowing
○ Hypercolumns of the cerebral cortex that contain highly connected neurons. A
neurons is more interconnected to other neurons in it’s column versus neurons in
other columns. (neurons that wire together fire together)
○ Limbic system? https://www.brightfocus.org/alzheimers/infographic/brainanatomy-and-limbic-system
Lecture 5
● Describe 2 types of changes: executive/motor/sensory/emotional - communication
changes caused by Linda’s stroke
○ Executive - Has to think critically about each step in each movement. Not make a
peanut butter and jelly sandwich but ‘pick up the bread, put in on the plate… etc”
○ Motor- right after stroke; completely paralyzed. Feels like everything tight all the
time. Couldn’t relax her muscles enough to move “not that you can’t feel your
body, it’s that you can’t relax your body to move it” - very stiff and draining.
○ Sensory - ???
○ Emotional - right after stroke; couldn’t control emotions. Would laugh and cry are
at inappropriate times
● List cranial nerves along with the targets they innervate
○ above
● Explain the organization of the spinal cord segments related to sensory innervation and
motor output
○ Spinal cord
■ vertebrae
● 7 cervical vertebrae - more motor neurons
● 12 thoracic vertebrae - more motor neurons
● 5 lumbar - more sensory neurons
● 5 sacral - more sensory neurons
■ Motor neurons are in ventral horn of spinal cord
● Pain and temperature
● Fine touch and proprioception
● Visceral (internal organs) sensation
● Visceral (internal organs) motor
■ Sensory neurons are in the dorsal horn of spinal cord
● Somatic motor to distal limb mm
● Somatic motor to proximal limb mm
● Somatic motor to axial mm
■ More central neurons govern areas more close/internal to the body.
Further out neurons govern more out parts (Ex. fingers and toes)
●
●
●
■
○ Cervical and posterior sacral have enlarged unstained areas (which are cell
bodies/dendrites) which is because they have more neurons because they need
to send and receive more signals from the limbs.
○ Spinal cord and associated ganglia
■ Ganglia- Where sensory cell bodies are and send axons into core of
spine
● Sympathetic ganglia - contains autonomic motor neurons
● Dorsal root ganglia - contain cell bodies of afferent sensory
neurons
Explain how structure-function relationship identified Broca/Wernicke/memory
○ Form fits function. Found via patients of B&W.
○ Found via lesions (see below)
Differentiate symptoms of stroke from those traumatic brain injury
○ Stroke - when blood supply to part of the brain is interrupted or reduced
depriving brain tissue of oxygen and nutrients.
■ Hypoxia - partial or complete lack of oxygen/blood to the brain
■ Ischemia - when blood flow to the brain is compromised leading to a
further decrease in O2
■ Types of stroke
● Ischemic stroke (80% of ischemic strokes are fatal) less common
- arteries get narrowed or blocked
● Hemorrhagic stroke- arteries leak/rupture
● Transient ischemic attacks (TIAs)- transient blockage
○ Transient: A transient event is a short-lived burst of energy
in a system caused by a sudden change of state. A stroke
that only lasts a few minutes.
■
■
■
■
Symptoms - FAST, trouble speaking and understanding, paralysis or
numbness of the face or arm or leg, trouble seeing in one or both eyes,
sudden and severe headache, trouble walking,
Intervention needs to be within 6 hours of insult
Insult ● Immediate damage - necrotic cell death
○ Primary neuron loss aka necrosis due to influx of Ca and
massive release of glutamate (major excitatory transmitter
in the brain)
○ Necrosis - cell swells, cell becomes leaky, cellular and
nuclear lysis causes inflammation
● Delayed damage - apoptotic cell death
○ Secondary neuron loss aka apoptosis due to glutamate
but also enzymes (proteases, phospholipases,
endonucleases, caspases), reactive oxygen species (ROS)
○ Apoptosis - cell shrinks, chromatin condenses, ‘budding’,
apoptotic bodies are phagocytosed, no inflammation
Mitochondrial dysfunction is critical to neuronal death
● Stress causes mitochondrial permeability transition pore (mPTP)
to open, thus releasing cytochrome C thus apoptosis.
● Stress can also cause Ca 2+ and ROS to escape leading to
necrosis
● Transient receptor potential melastatin 7 (TRPM87) is upregulated by neurons, reacts to ROS (as released above), thus
causing cell death.
○ Experimental down-regulation of TRPM7 increases
neuronal survival during prolonged anoxia. Current
therapeutic target affect blood flow, but if TrpM7 can be
suppressed
○
○
ROS - Reactive oxygen species (ROS) are well known to elicit a
plethora of detrimental effects on cellular functions by causing damages
to proteins, lipids and nucleic acids. Neurons are particularly vulnerable
to ROS, and nearly all forms of neurodegenerative diseases are
associated with oxidative stress
Traumatic Brain Injury (TBI)
■ An alteration in brain function due to an external physical force that leads
to a varied array of symptoms (mild, moderate, severe)
■ Symptoms
● Mild TBI - less than 30 min loss of consciousness, less than 24
hours of memory loss
● Moderate/severe TBI - over 30 min LOC, over 24 hours of
memory loss, coma, convulsions or seizures, dilation of one of
both pupils, CSF and blood draining from the nose or ears, loss of
feeling in extremities, slurred speech
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■
■
■
■
■
■
either/both - headache, nausea, vomiting, changes in sleep,
confusion, LOC, poor concentration, sensitivity to light or sound,
2 types
● Open head injury
○ Penetration of the head, causes localized brain damage,
result in discrete and relatively predictable disabilities,
○ common causes; severe fall, gun shot, assault
● Closed head injury
○ No open head wound, brain damaged internally, causes
diffuse tissue damage, resulting in generalized and highly
variable disabilities
○ Common causes: falls, vehicle accidents, sports accidents
Imaging
● edema (fluid build up) and a shifted brain (CT scan). TBI induced
changes in the blood brain barrier are stimulated not only by the
impact, but also by inflammatory and immunological signaling
BBB
● Edema will affect blood brain barrier. Astrocyte, pericyte, neurons,
and friends make tight junction surrounding blood vessels.
● loose junctions - leukocytes are WBC
Inflammatory signaling (Immune signaling by microglia and the BBB)
● Microglia are the immune cells of the CNS (BBB keeps out
almost all other immune cells). They get ‘activated’ by cytokines in
the interstitial space to alter adhesion complexes in the BBB and
stimulate inflammatory signaling
● Astrocytes (another glial cell) also contribute to inflammatory
signaling.
○ Mitochondrial dysfunction - less ATP, more ROS, thus
energy failure and oxidative stress
○ Energy depletion causes demyelination of
oligodendrocytes thus axonal death
○ Energy depletion causes apoptosis via oligodendrocytes
○ NEURODEGENERATION
SUMMARY of physiological changes post-TBI - Neuronal damage, cell
death, axonal injury, information processing defects, inflammation,
increased vascular permeability, increased BBB permeability, increased
pressure
Repeat TBI
● Foreign cells from outside the brain to enter the CNS (T cells, B
cells, other leukocytes, which may increase inflammatory damage)
○ Inflammation in the body when the BBB is leaky can have
similar effects
●
●
Damage to primary sensory cortices, amygdala, and hippocampus
(together) can stimulate or replicated PTSD (insomnia, flashbacks,
increased startle response, distorted thoughts)
Multiple TBIs correlate with alzehimer’s like pathology (plaques
and tangles) and even Chronic traumatic encephalopathy (CTEneurodegenerative disease involving Tau)
○
Lecture 6
● distinguish between the Wernicke’s and Broca’s based on the lesion effects
○ Experientially - lesion method helps identifies function of specific brain regions.
Damage to a particular part of the NS, see defects and then can decipher what
connections it has and what that area does
○ Healing a damaged brain can heal physiology/behavior, can the brains innate
healing mechanisms be boosted? How axons once severed can regrow.
■ Motivate people who have spinal cord injuries. Lesion in spinal cord, put
electrode and stimulate distal to lesion to get individual very excited. Thus
cell bodies will regrow and synapse out in peripheral to lesion.
○ Paul Broca’s patient could only say ‘tan’ but language comprehension was
normal. Thus Broca’s area - speech formation
○ Carl Wernicke’s patient has normal speech but altered language comprehension.
The wernicke area - understanding language.
○ Conduction aphasias - the axons that affect wernicke's area to broca's area.
○ Henry Molaison- removed hippocampus and amygdala to reduce grand mal
seizures. Long term memory was lost, loved to be studied.
● explain why the hippocampus is associated with declarative memory
○ Henry Molaison - have severe seizures, gone when hippocampus and
amygdala was recessed.
■ Can’t remember motor tasks, but could retain procedural memory
encoded by cerebellum
● differentiate between apoptosis and necrosis at the cellular level
○ Apoptosis - cell shrinks, chromatin condenses. Becomes phagocytosed, no
inflammation.
○ Necrosis - cell swells, Cellular and nuclear lysis causes inflammation. Leak out
potassium ion, when get inflammatory response, hard to get that down
● explain why TrpM7 and mitochondria are therapeutic targets for limiting neuronal death
○ Transient receptor potential melastatin 7 (TRPM87) is up-regulated by
neurons, reacts to ROS (released by stress), thus causing cell death
○ Experiment down-regulation of TRPM7 increase neuronal survival during
prolonged anoxia. Current therapeutic target affect blood flow, but if TrpM7 can
be suppressed….
● differentiate between open/closed, mild/severe TBI based on symptoms
○ Open - open wound duh, penetration of the head. Causes localized brain
damage, result in discrete and relatively predictable disabilities
○
○
●
■ Common causes: sever fall, gun shot, assault
Close- no open head wound duh. Brain damaged internally, causes diffuse tissue
damage, resulting in generalized and highly variable disabilities
■ Common causes: falls, vehicle accidents, sports accidents
symptoms
■ Mild TBI - less than 30 min loss of consciousness, less than 24 hours of
memory loss
■ Moderate/severe TBI - over 30 min LOC, over 24 hours of memory loss,
coma, convulsions or seizures, dilation of one of both pupils, CSF and
blood draining from the nose or ears, loss of feeling in extremities, slurred
speech
■ either/both - headache, nausea, vomiting, changes in sleep, confusion,
LOC, poor concentration, sensitivity to light or sound,
describe how the BBB limits material/cells from entering the brain and the consequences
of leaky BBB during TBI
○ Contains tight junctions that get lost due to inflammation upon TBI. Thus letting in
● explain why inflammatory processes are therapeutic targets during TBI
Lecture 7
● Explain the basic mechanisms underlying electroencephalography (EEG) recordings
○ EEG: recording electrical activity.
■ https://www.slideshare.net/kj_jantzen/biophysical-basis-of-eeg
○ Surface potential recordings from specific location.
○ Brain is a very good insulator so very little gets through, but what does does in
microvolts.
○ Event Related Potentials: electrical activity at brain locations that can be
correlated with a task
○ Peaks/troughs are sometimes referred to the time of occurrence.
○ Generated by… excitatory dendritic currents.
■ Apical dendrite acts as a dipole
■ Dendritic currents, not action potentials, some are at best
■ Electrical signal is strongly attenuated at the scalp
■ Inhibitory neuron populations do not produce good dipoles
■
■ Based on genetic modeling- apical dendrites have loops of currents,
creating EEG signals
● Explain the basic properties and types of seizure with an idea of mechanism
○ Seizure - spontaneous electrical that shows high frequency EEG activity.
○ Epilepsy - multiple seizures
○ Seizure types
■ Partial seizures
● Simple partial - focal with minimal spread, person is conscious
●
●
●
●
Complex partial - focal but spreads, may start with blank stares
and random motor activity, conscious but unaware of
surroundings
■ Generalized seizures
● Tonic-clonic - grand mal, person cries out, falls, appears rigid,
followed by muscle jerks, shallow breathing, bluish skin, and
sometimes loss of bladder control
● Absence - petit-mal, blank stare, lasts a few seconds
● Atonic - sudden loss of postural tone leading to collapse, 10s min
● Clonic-myoclonic - brief, massive muscle jerk off whole or part of
the body
● Infantile spasms - quick movements arising between 3 months
and 2 years
■ Continuous
● Status epilepticus - over 30 minutes, or 2 or more sequential
seizures without full recovery, often requires medical intervention
to prevent hypoxic injury
○ Don’t want brain to become hypoxic (that the brain uses up ATP and can’t
replenish it fast enough)
Neuron’s goal
○ Maintain homeostasis in ways similar to all cells but also charge
○ Store information in proteins but also in voltage and voltage changes
○ Respond appropriately with changes in current, voltage, neurotransmitter release
Define membrane voltage, membrane current, and membrane resistance
○ Membrane voltage- created by separation of charge (ions cannot pass through
neuronal semi-permeable membrane so they hang on the sides and get super
attracted/repulsed by each. Membrane is an excellent insulator so mV created)
○ Membrane current - movement of charge (due to voltage). (like electrons
flowing across a certain channel). Fast-moving charges that move over time
makes a larger current) (I, mili-amps, mA)
○ Membrane resistance - current will move more slowly when it feels resistance.
Pinch a straw- more resistance, let the straw loss - less resistance.
■ + charges don’t flow as easily
Use Ohm’s Law to describe the effects of changing voltage, current, and resistance
○ V=IxR
○ Relates to movement of a charge across the lipid bilayer with the voltages across
that same membrane.
○ Charge movement across the membrane produces a voltage changes. A voltage
change causes charge to flow across the membrane.
Other
● Log of N to memorize
○
○
○
E ion = 58 log [ion in / ion out]
Chemical Gradient vs Electrical Gradient
Ohm’s law - says that since R is constant (channel is always open) we get a
linear relationship between movement/current and membrane voltage
●
Lecture 8
● Define electrochemical gradients and use this understanding to solve basic problems of
ionic flow (direction, estimation of magnitude)
○ Has a chemical gradient (wants to go where less of its own is) and electrical
gradient (wants to create no charge, charge 0)
○ “Thus, the movement of potassium ions across the neuronal membrane is
governed by two oppossing forces: (1) the concentration gradient for potassium
tends to push potassium out of the neuron, and (2) the electrical potential
gradient across the cell membrane tends to move potassium ions back into the
neuron” (pg 37)
○ Electrochemical gradients: The chemical portion comes from ions wanting to
be in equal ratios on either side of the membrane. Electro portion comes from the
desire to be as close to voltage of zero as possible (ions ‘balance each other
out’).
○ Estimation of magnitude??- Use graph to figure out what the current is at ‘x’
voltage membrane (Vm)
● Use linear I-V plots to identify Nerst (reversal) potential, current/voltage, amplitude, and
direction
○ “Charge separation creates reversal potentials” (slides)
○
●
●
●
●
“IPSPs (inhibitory postsynaptic potentials) can be depolarizing rather than
hyperpolarizing. The point at which they switch polarity is called the IPSP
reversal potential” (pg57).
○ Reversible potential = equilibrium voltage
Describe and use the nernst relationship between voltage and concentration with linear
I-V plots
○ Slope is G - conductance aka how easy it is for ion to get across membrane
Differentiate conductance from resistance; use conductance to compute currents
○ Conductance is 1 over the resistance. G = 1/R.
○ I na/ (Vm - Ena) = Gm
○ Driving force - on the slope line, how much u want to get to the x=0 (subtraction)
Define permeability and describe the ionic/voltage relationship s related in the GoldmanKatz equation
○ Permeability (P): reflects the state of the membrane for ion passage. (how many
channels are open at any instant in time- how easy it is for ions to pass through
the membrane.
○ This equation determines the reversal potential across a cell membrane taking
into account all the ions that are permeable across that membrane
Other
○ Neurons are generally at -70 mV (at rest), but will momentarily surge to +40 mV
(generating an action potential).
○ Ions will get water shells (smaller the ion (mass) the stronger the electrostatic
field strength at their surfaces) (higher charge to mass ratio)
■ This water will be shed at entrance of ion channel via selectivity filter
(charged amino acids get the job done)
○ As cell gets more negative, sodium leaks
○ Ion channels regulate resting membrane voltage
■ Ex. K2P subunits allows K+ to flow in and out…
○ Patch-clamp electrode
■ Can track current (aka flow) through a single ion channel
■ Create super tight clamp with a super tiny pipette tip with a sensitive
amplifier on the inside of it. Carefully cleaning the pipette and the cell
membrane prevents leakage of ions.
■ Have resistance
■ Use the tiniest bit of suction
■ Can alter ion and transmitter concentration in pipette and extracellular
fluid thus observing fluid composition, Vm, frequency, duration etc.
■ Revolutionized the study of electrically excitable membrane
○ Specific Ion channels - LEAKAGE CURRENTS
■ K2P subunits regulate K+ leakage, 2 pore domain
■ NALCN mediate Na+/Ca2+ leakage
● 4 sets of 4 ™ subunits, 4 pore domains, one
● Gain of function mutations, high neuronal activity, seizure
●
■
Loss of function mutation, low neuronal activity, flaccidity and
altered consciousness
Action potential (ap)
● Generated by ion channels that RESPOND to Vm. When Vm
passes a certain threshold of excitation (as the neuron
depolarizes) a positive feedback loop create ap.
Lecture 9
● explain how information is encoded by
○ AP firing/spiking frequency.
■ “AP firing frequency increases with larger depolarization”
● explain 2 ways in which the Na current mediating action potentials can be isolated
○ For Na current to flow : activation gate must open, inactivation gate must not be
closed, Activation voltage = Vm thus opening the activation gate
■ Inactivation gate: a protein subunit that physically flips into the channels
thus inactivation it. Loop
● describe the charge movements associated with the action potential
○ When the leakage current from K+ and Na+ reach the voltage of the threshold of
excitement, the Na+ voltage gate channel will open, Na+ floods in. The interior is
depolarizing/gets overly positive, thus K+ voltage gated channel will open and K+
will flow out while in the peak, hyperpolarizing the neuron. The voltage first
overshoot then come back to the resting membrane potential.
● describe basic molecular and physiological properties of voltage-gated Na channels
○ 4th segment of the 6 transmembrane regions of the Na+ channel protein
monomer. - it has LOTS of positive charges in the alpha helices that span the
membrane. --- The segment is shifted down because the inside of the cell has a
lot of negative charges. As Potassium (K+) flows out, Transmembrane region 4
will shift up.
● Something about Vrest = E something with current? Not really sure oops
●
○
Other
○ How to study ion current relate to AP
■ Current-clamp recording: holds I at a constant value while measuring
voltage. Inject specific amount, Pass V threshold, record APs.
■ Voltage-clamp recording: holds Vm (voltage membrane) at a constant
value while measuring current. Inject charge very fast to force Vm to
specific voltages, record charges moving in or out of the cell.
○ Patch Recording - detects currents and voltage though the whole cell’s
membrane, a small path, or a single ion channel via a recording glass pipette
○
Lecture 10 - refractory periods
● describe basic molecular and physiological properties of voltage-gated Na channels
(activation voltage, activation/inactivation gate, TTX)
○ activation/inactivation gate- 4th segment of the 6 transmembrane regions of
the Na+ channel protein monomer. - it has LOTS of positive charges in the alpha
helices that span the membrane. --- The segment is shifted down because the
inside of the cell has a lot of negative charges. As Potassium (K+) flows in,
Transmembrane region 4 will shift up.
○ Activation voltage
○ TTX - a sodium channel blocks, a toxin, - learning about this in Ecology too
●
●
○
○ Blocks Na channels, leaving K current intact
describe the basic molecular and physiological properties of delayed-rectifier K channels
(activation voltage, lack of inactivation, TEA)
○ Action potentinals involve a outward K+ current
○
○ Activation voltage
○ Lack of inactivation- Ik delayred rectiffier current, these channels open and
don’t lose until Vm is repolarized after AP (aka current goes up and stays there,
will only decrease when repolarized)
○ TEA- blocks the K+ chanel
■ If the K+ channels are blocked, it prevents the repolarization of Vm, thus
Na channels stay in inactiated state
■ TEA also increases the duration of a propagated action potential but has
no effect on its speed of propagation
■ Do you want TEA? oK.
■ High concentration of TEA gives 1 spike, because of inactivation.
● What does Tea exactly do?
○ Inhibits K+ channels, but since the neurons cant
hyperpolarize, Na+ will continue to flow in.
explain what is meant by action potential refractory period
○ Times after a spike when their generation is impossible (absolute) or more
difficult (relative). There is a delay between spikes, if you try to stimulate it too
early, you won’t get an AP. if wait but not long enough, will get a small AP.
○ Due to how many ion channels are inactivated at the time (inactivated via a
protein pieces that ‘plugs’ the channel for a refractory period. - opening is
RANDOM (stochastic)
○
●
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During that time - repolarization of membrane, closure of gate, and displacement
of channel-inactivation segment
differentiate the absolute and relative refractory periods
○ Absolute refractory periods - stimulus and NO spike in Vm
○ Relative refractory periods - stimulus and lil spike in Vm, but not enough for an
action potential
○
explain the physical bases for these periods
○ The neuron has to remove the inactivation gate and then hyperpolarize to be
ready for another AP
give two examples of how refractory periods affect AP propagation
○ If you try to produce an AP in the refractory period, too soon won’t at all/will
produce a little bit.
explain what determines AP conduction velocity and how myelination affects
propagation speed
○ Action Potential Conduction velocity is related to fiber size because larger
axons have lower internal resisitence. Diameter bigger, more charges will flow,
will depolarize area above the region faster.
○ Myelination causes saltatory action potential conduction (<< is the propagation
of AP along myelinated axons from one node of Ranvier to the next). Charge go
along axon, can hyperpolarize at node of ranvier (the dip/gap in between the
myelin sheath ‘bumps’). Spikes appear to jump between the nodes of Ranvier.
■ No charge leaks out from myelin
■ Next node is depolarized to almost the same extent as the previous one.
■ When have myelin, current HAS to flow to the next mode (vs getting lost
in the sauce aka escaping from any point on the revealed axon (aka a
naked neuron)
○ Myelination increases AP propagation velocity in smaller axons (aka the signal is
faster when its myelinated)
○
compare and contrast voltage-gated Ca channels with Na channels
○
Ca
-
-
-
-
●
Both
Na
Too much Ca
influx can cause
degeneration and
impair axonal
transport
Allow Ca in when
Vm depolarizes
Can artificially
add Ca to
neurons and
measure
neuronal activity
(genetically
tagged Ca)
Ca channels and
currents are
common in the
cell body,
synaptic
terminals, and
dendrites
How do
fluoroscopy! tagged Ca ions
○
Other
○ How to increase the number of Na channels that can open?
■ Hyperpolarize beforehand, so the change is bigger thus response is
bigger.
○ Orthodromic Propagation - from initiation zone to the axonal terminals
○ Antidromic Propagation - in the reverse direction (rare)
○ Peripheral Neuropathies: genetic and acquired loss of peripheral nerve function
○ LVA - low voltage activation
○ HVA - high voltage activation (located in cell bodies, dendrites, and axons