Principles of Cell and Systemic Physiology (Lectures 2-3)
1. The plasma membrane is the phospholipid bilayer + all the associated proteins and other
molecules. Many of these are transmembrane proteins. Collectively, these components
confer selective permeability to ions, glucose and other molecules.
2. The nucleus hosts the genome and is the site of transcription which produces mRNAs that
are exported.
3. Ribosomes are sites of protein synthesis (translation). Ribosomes are found studded on
endoplasmic reticulum (ER) or free in the cytoplasm.
4. The ER/Golgi complex uses a vesicle-based system (budding and fusion) to sort new
proteins to either the PM, the outside of the cell (soluble proteins released by exocytosis) or
lysosomes. The cytoplasm and other organelles get their proteins from free ribosomes
(mitochondria make a few proteins from their own mini-genome and
transcription/translation apparatus).
5. Mitochondria produce ATP from glucose or fatty acids (it can use amino acids in a pinch). All
you need to know regarding the metabolic pathways leading to oxidative phosphorylation
are summarized on a single slide i.e. you do not need to know the enzymatic details of
glycolysis, Krebs cycle and electron transport.
6. Lysosomes digest debris by fusing with intracellular vesicles often derived from endocytosis.
7. Peroxisomes detoxify free radicals.
8. The cytoplasm consists of the semi-liquid cytosol, an aqueous compartment in which
intermediate metabolism occurs, the organelles and the cytoskeleton.
9. Microtubules are dynamic polymers of tubulin. They form highways for movement of
transport vesicles via kinesin and dynein motor proteins, and cilia and flagella for generating
movements.
10. Microfilaments are dynamic polymers of actin. In association with myosin, a motor protein,
they produce cellular contraction e.g. muscle fibers.
11. Intermediate filaments are longer proteins produced by an array of different genes.
12. Complex multicellular life, like humans, requires many different types of cells specialized for
different tasks. Differential gene expression is the proximate cause: all cell types contain the
same DNA, but express unique subsets of ~10K genes for any given cell type (out of ~22K in
the genome).
13. The basic definition of each level of organization: cell, tissue, organ, organ system,
organism.

cell: the basic unit of life enclosed by a membrane that can obtain fuel, exchange materials, intracellular transport, metabolize, synthesize proteins, and reproduce

tissue: a group of cells that possess a similar structure and perform a specific function including 4 types — muscle (contraction), nervous (initiate/transmitting electrical impulses), epithelial (exchange across barriers and to secrete substances), connective (support).

organ: body structure that consists of different tissue types

organ system: collection of organs that preform related functions

organism: the highest level of biological complexity, where all the different parts of a living being, including cells, tissues, organs, and organ systems, work together to form a complete, independent individual capable of carrying out life functions.
14. You do need to know the concept of homeostasis including its purpose, components
(sensor, integrator, set point, effector), difference between intrinsic and extrinsic control,
and the concept of negative feedback.

The tendency of a system to maintain internal stability by having a coordinated response to any situation or stimulus that would disturb its normal condition or function.

Factors that must be maintained — conc. of nutrients, conc, of O2 and CO2, conc, of waste products, conc, of water and electrolytes, pH, temperature, volume/pressure, defense against foreign invaders.

Intrinsic — local control systems “built in” to an organ or tissue.

Extrinsic — external control system outside of an organ permitting coordination regulation of several organs.

Negative Feedback — the control action decreases the effect of any disturbance (the response opposes the change).

Sensor: mechanism to detect the controlled variable.

Integrator: compares the sensor’s input with the set point.

Set Point: The desired range of the controlled variable.

Effector: Adjusts the value of the controlled variable.
15. The three main types of communication via extracellular chemical messengers (hormonal,
paracrine, synaptic) which differ in their spatial range.

Hormonal: Hormones travel through the circulatory system to reach their distant target cells.

Paracrine: Cell secretes a signaling molecule into the extracellular fluid that affects nearby cells. The signaling molecule, called a paracrine factor, diffuses over a short distance.

Synaptic: A chemical signal travels between nerve cells at a synapse in response to electrical signal. The presynaptic cell releases neurotransmitters into the synaptic cleft, which are then transported across the synapse to bind to receptors on the postsynaptic cell.
16. The basic features of nuclear receptors, GPCRs (not the details of the example pathways),
enzyme-linked receptors and ionotropic receptors.

Nuclear Receptor: (intracellular) that activates gene expression.

GPCRs: (cell surface) G protein coupled receptor that detect extracellular signals like hormones, neurotransmitters, and light, and then transmit this information inside the cell by activating intracellular signaling pathways through the interaction with G proteins; essentially acting as a communication channel between the cell's external environment and its internal functions.

Enzyme: (cell surface) linked receptors.

Ionotropic Receptors: (cell surface) ion channels.

Membrane biophysics (Lectures 4-8)
1. The brain receives sensory signals, processes them and produces motor output. Perception
is defined as what you can report e.g. the perception of faces warping during electrical
stimulation of the face area of human cortex. The brain relies on neurons specialized for
chemical and electrical signaling. The 86 billion neurons in the human brain and
interconnected by 100+ trillion synapses where a chemical neurotransmitter is released by
one neuron and detected by another (note: electrical synapses also exist).
2. Ion movement across the plasma membrane is the basis of electrical signaling in neurons.
3. There are two types of transmembrane proteins for ion/molecule movement: carriers and
channels.

Carriers: mediated transport that escorts molecules across the membrane that needs assistance.

Channels: permeable to specific ions such as Na+ or K+
4. Carriers have binding site for the molecule to be transported: (1) Facilitated diffusion uses a
fixed affinity site and transports down the concentration gradient. (2) Pumps have variable
affinity sites and transport uphill, against the concentration gradient.
5. The Na/K ATPase is a pump that transports 3 Na out and 2 K in with each turn of the cycle.
Its role is to establish and maintain concentration gradients.
6. Ion channels do not have binding sites. They have pores which allow for diffusion-like
permeation.
7. Ions move in response to two driving forces: chemical driving, which is diffusion down a
concentration gradient, and the electrical driving force which results from electrostatic
interactions at a distance. At any moment, each driving force can be represented as a vector
which has direction and magnitude. At any moment, ions experience a net driving force
which is the vector sum.
8. Neurons have a membrane potential which results from charge separation across the
membrane. By convention the polarity is referenced inside relative to outside e.g. at rest
there is an excess of negative charges on the inside and excess of positive charges on the
outside, for a resting potential of -70 mV.
9. The amount of charge separation underlying biologically meaningful electrical signaling is
extremely small compared to the total number of ions in bulk solution on both sides of the
membrane. Therefore, Na and K concentration gradients do not run down during normal
physiological operation.
10. Ions have an equilibrium potential, defined as the membrane potential at which there is no
net charge movement for that ion. Its calculated using the Nernst equation. You need to
know the direction and relative magnitudes of the concentration gradients for Na and K,
and how to apply the Nernst equation. You do not need to memorize either the Nernst or
GHK equations and will you not need a calculator.
11. Cells have a resting membrane potential (RMP) which depends on all the permeant ion
species weighted by their relative permeabilities. At rest, K permeability dominates as there
are more K leak channels than Na leak channels. RMP is calculated using the GHK equation
(see above).
12. Transient injection of current leads to passive dissipation of current regardless of the
current source. This passive dissipation causes a graded potential, which always decreases
in size as it flows away from the current source. Graded potentials are self-limited in time
and space.

13. Action potentials (APs or ‘spikes’) are ‘all or none’ electrical signals initiated at the axon
hillock which rapidly propagate to the axon terminals (as far as 1 meter) where they trigger
transmitter release. That last bit is important: the brain is a synaptic network.
14. APs depend on voltage-gated Na and K channels. The complete linear sequence of events
underling APs is important to know (8 top and bottom panels on two consecutive slides).
These channels produce voltage-dependent, time variant changes in membrane
permeability to Na and K.
15. Net driving force on Na is strong at AP onset but weak at AP peak. The opposite is true for K.
16. The absolute refractory period is the epoch, 1ms in duration, during which the neuron
cannot fire another AP regardless of the strength of the new triggering event. It begins
when all Na channels have opened (occurs just after threshold is reached) and ends when
Na inactivation is removed.
17. The relative refractory period is the epoch, a few ms in duration, during which the neuron
can fire another AP but would require a larger than usual triggering event. It begins when
Na inactivation is removed and ends when the resting potential is restored following K
channel deactivation.
18. The speed and reliability of AP propagation depends on axonal diameter, membrane
resistance, internal resistance and the presence or absence of myelin.
19. Contiguous conduction relies on a continuous distribution of v-gated Na and v-gated K
channels along the length of the axonal membrane. One metaphor is the stadium wave.
This is an active process in the sense that it is not self-limited in time and space.
20. Saltatory conduction relies on myelin (insulator) and clusters of v-gated Na and v-gated K
channels found at the Nodes of Ranvier. This is an active process at the sites of initiation
(axon hillock) and nodes of Ranvier, and a passive process (graded potential) underneath
the myelinated stretches of axon.
21. How far current will flow down the axon before leaking out depends on the relative values
of membrane resistance (sometimes referred to as transverse path) and internal resistance
(the axial path). In giant axons, internal resistance low which favors AP propagation. In
narrow axons like those in our brains, internal resistance is high which favors leak out and
poor propagation. Myelin increases membrane resistance such that the axial path is now
the lower resistance path.
22. Myelin also decreases capacitance and therefore lowers the time constant which results in
the membrane potential changing faster in response to current injection: it speeds up AP
propagation.
23. Na channel inactivation ensures unidirectional spread of naturally occurring AP, and the
annihilation of APs experimentally induced at either end of an axon when they collide.
24. Demyelinating diseases result in slow and unreliable AP propagation. The autoimmune
disease multiple sclerosis commonly affects the cerebellum, a brain structure which plays
an important role in calibrating ongoing movements. The symptoms = ‘action tremors’

Synaptic transmission (Lectures 9-10)
1. Synapses are connections between a neuron and target cell that allow for communication.
2. Chemical synapses permit direct ‘electrical coupling’ between two cells. Proteinaceous
tunnels built from connexin proteins allow passive current flow from one cytosol to the
next. These tunnels are much larger than ion channel pores. Cardiac cells are electrically
coupled to form a syncytium. The mature brain, in contrast, relies mostly on chemical
synapses.
3. Know the mechanisms underlying synaptic transmission! FYI, neurotransmitter release via
Ca-dependent exocytosis is also referred to as excitation-secretion coupling. Arrival of AP at presynaptic terminal, calcium flows into presynaptic terminal, neurotransmitter diffuses across synaptic cleft, neurotransmitter binds to postsynaptic receptor, permeability of membrane of postsynaptic neuron is altered, neurotransmitter is released by exocytosis.
4. Transmitter receptors can be ionotropic (receptor is the channel) or metabotropic (receptor
activates G protein cascade which acts on a separate ion channel). EPSPs bring the cell
closer to threshold for firing a spike, IPSPs bring it further away.
5. The most common ionotropic glutamate receptor allows both Na and K to permeate. The
dominant charge carrier is Na due to its larger net driving force in and around resting
potential. The results in depolarization. The reversal potential is ~ 0 mV which is well above
threshold for firing a spike, therefore the effect is excitatory.
6. Ions have equilibrium potentials. Channels have reversal potentials. At those values, there is
no net current flow.
7. The most common ionotropic GABA receptor is permeable to Cl. The reversal potential is -70, which is below threshold for firing a spike, therefore the effect is inhibitory. Many
metabotropic receptors activate K channels. The reversal potential is -90, which is below
threshold for firing a spike, therefore the effect is inhibitory.
8. Define convergence and divergence. Convergence: synaptic input of many neurons to one neuron. Divergence: synaptic output of one neuron onto many neurons
9. Postsynaptic neurons in the brain tend to experience an intermittent bombardment of 10s-
100s of synaptic potentials which are individually small. These PSPs add (or subtract) from
one another when they occur close together in time and space - conditions needed for
spatiotemporal summation.
10. Summed PSPs that reach threshold will cause a spike to be fired from the axon hillock, as
illustrated in the synaptic transmission experiment.
Brain organization (Lecture 10)
1. Slide 3 is a useful block diagram.
2. Afferent = ascending towards the brain; efferent = descending away from the brain. That is
true at any level of the neuroaxis. At the level of the spinal cord, afferent sensory input goes
through the dorsal root ganglion and efferent motor output goes thru the ventral roots.
Note the spinal cord (and brain) are bilaterally symmetric.
3. Define functional localization and topographic map. Localization of function is the idea that certain functions (e.g. language, memory, etc.) have certain locations or areas within the brain. topographic map is the ordered projection of a sensory surface (like the retina or the skin) or an effector system (like the musculature) to one or more structures of the central nervous system. Topographic maps can be found in all sensory systems and in many motor systems.
4. The autonomic nervous system will not be covered on midterm 1. That said, slide 11 uses
the ANS to make an important, universal point: chemical messengers are not inherently
excitatory or inhibitory as the effect depends on receptor identity.

Sensory systems (Lectures 11-12)
1. Receptor cells (photoreceptors, hair cells, somatosensory receptors) are specialized to
transduce a particular form on environmental energy (‘modality’; light, sound, touch) into a
change in membrane potential. That is a receptor potential. Receptors are grouped
together in sheets referred to as ‘sensory epithelium’ or ‘sensory surface’ (retina, cochlea,
skin).
2. Receptor potentials cause action potentials to be generated in the receptor cell or its
downstream target. The rate and timing of action potentials carry information about the
stimulus to the brain.
3. The thalamus is an obligatory relay of visual, auditory and somatosensory information to
primary cortices, defined as the anatomical targets of the thalamic subdivisions. Primary
cortices project to higher levels of cortex where multimodal and other perceptions are
formed.
4. The receptive field of a neuron at any level of the nervous system is the range of locations
on the sensory surface that, when stimulated, alter the neuron’s activity.
5. Lateral inhibition is a universal circuit motif that sharpens receptive fields via side channel
suppression.
6. Acuity is your ability to discriminate two similar but not identical sensory stimuli. It depends
on receptor density and receptive field size.
7. The spatial organization of the sensory surface is maintained at higher levels of the brain.
These are called topographic maps. You can think of the topographic axonal projections as
labelled lines (i.e. each has a unique identifier).
8. Visual system: pupil size gates the amount of light coming into the eye. Light is focused by
the lens on back of eye which houses the retina. It’s a 2D camera trained on your visual field
(the full range of what you can see).
9. Light passes through the retinal circuitry and is absorbed by photoreceptors, rods and
cones. Know their contrasting functional properties.
10. In both rods and cones, light is absorbed by photopigments which activate a G protein
cascade that enzymatically cleaves cGMP. In the dark, the cGMP had been holding open a
Na channel which had depolarized the cell leading to transmitter release. It’s an inhibitory
neurotransmitter (actually glutamate!) and had been suppressing the downstream neuron.
In the light, transmitter release stops and the circuit is disinhibited (the downstream cell is
intrinsically active). That causes retinal ganglion cells to fire spikes. RGC axons gather
together and leave the retina at the optic disc. Fun: go online and find your blind spots.
11. RGC axons project all the way to thalamus. On the journey, medial axons cross the midline.
Thus, the information content of the optic nerve, optic chiasm and optic tract are different.
This is a classic example of damage-deficit correlation! Know it.
12. The thalamus project to primary visual cortex which contains a topographic map of the
retinal surface aka ‘retinotopic’ or ‘visuotopic’ map. That is also a map of where the
photons came from i.e your visual scene. Though not covered in class, FYI, visual activity
percolates out from primary cortex along ‘what’ and ‘where’ pathways, involved in building
complex percepts.
13. Auditory system: sound is a wave with alternating cycles of compression and rarefication of
particles in a medium (e.g. air or water). Sound is reflected by your pinna into the ear canal and causes the tympanic membrane to vibrate. Vibrations are conducted via the
mechanically efficient ossicles to the oval window which causes fluid movement within the
cochlea. This causes the basilar membrane to move up and down. Important: there is a
gradient in the physical properties of the basilar membrane that make different locations
resonate with different frequencies of sound. The narrow, stiff end near the oval window
best resonates in response to high frequencies, the broad, compliant end near the
helicotrema best resonates in response to low frequencies. The entire length of the basilar
membrane is populated by hair cells. Their apical stereocilia are embedded it the tectorial
membrane who’s pivot point is offset compared with the basilar membrane. This creates a
shearing force that bends the stereocilia forward and backward with each sound cycle. The
stereocilia membranes have mechanically-gated ion channels that open with each cycle of
sound and depolarize the hair cell (yes, with K!). This is a receptor potential. It causes
transmitter release from the hair cells to the primary afferent fibers which head towards
the brain. A map of the cochlear surface is maintained up through primary cortex via
labelled line projections. This is a map of tones, not sound source locations.
14. Somatosensory system: many different types of somatosensory receptors are distributed
throughout the skin. Pacinian corpuscles are one type of touch receptor. Their membranes
contain stretch-activated channels that open in response to membrane deformation. This
depolarizes the cell which triggers spikes that propagate towards the spinal cord. In
response to a sustained stimulus, encapsulated receptor types rapidly adapt, meaning they
exhibit a brief ‘on’ and ‘off’ response. This is also called phasic signaling. Rapid adaptation in
pacinian corpuscles is due to slow mechanical separation of the overlying connective layers.
In contrast, non-encapsulated receptor types exhibited sustained responses, also called
tonic signaling. Rapidly-adapting receptor types are partially responsible for percepts as
described in class and on the sample midterm.
15. Somatosensory information crosses the midline exactly once on its journey to cortex. There, one finds topographic maps of the sensory surface (‘sensory homunculus’).
Motor systems (lecture 13)
1. Motor neurons exit the spinal cord via the ventral root ganglion and synapse onto skeletal
muscle. This is the final common pathway for both voluntary and involuntary movement.
2. Mechanisms of communication at the neuron-muscle synapse are very similar to neuron-
neuron synapses. This synapse is also called the neuromuscular junction and the
postsynaptic side sometimes called the motor endplate.
3. Two differences: EPSP are typically large enough to cause spikes in the postsynaptic cell
(muscle), and transmission is rapidly terminated with assist from acetylcholinesterase, an
extracellular facing enzyme that breaks down the transmitter, Ach.
4. In myasthenia gravis, autoimmune attack on Ach receptors cause muscle weakness. The
symptoms can be partially alleviated by systemic administration of neostigmine which
blocks acetylcholinesterase and therefore prolongs the dwell of Ach in the synaptic cleft,
increasing total activation of the spared Ach receptors.
5. Know the withdrawal and extensor reflexes:

Withdrawal reflex: Protects the body from tissue damage caused by painful or hot stimuli. When you touch a hot stove or step on a tack, the withdrawal reflex causes you to pull away without thinking about it. The abdominal muscles are the primary muscles involved in the withdrawal reflex. 

Extensor reflex: Helps shift body weight to the other side and coordinate leg movement when walking. The extensor reflex is also known as the crossed-extensor reflex. When you step on a nail, the leg that is stepping on the nail pulls away, while the other leg takes the weight of your body. This is because the extensor muscles in the other leg contract to help you maintain balance. 
6. Voluntary movement is initiated by the motor cortex which contains a topographic map of
body parts. Descending pathways cross the midline exactly once before innervating muscle.

7. The basal ganglia are involved with planning and initiation of movement, and suppression of
unwanted movement. Degeneration of this structure is Parkinson’s disease leads to resting
tremors and difficulty initiation movement.
8. The cerebellum compares the actual movement with the intended movement and makes
adjustments. Degeneration of this structure in multiple sclerosis leads to action tremors.
Higher brain functions
1. What is functional localization? What three methods have tested this hypothesis? Localization of function in the brain refers to the theory that specific parts of the brain control specific aspects of brain function.

-Functional magnetic resonance imaging (fMRI): Tracks neural activity and the brain's energy consumption.

-Electroencephalography (EEG): Records the brain's electrical activity, which can help detect brain disorders.

-Transcranial magnetic stimulation (TMS): Can be combined with neuroimaging tools to measure how stimulating one part of the brain affects other areas.
2. Know the saga of Phineus Gage. On the 13th of September 1848, while preparing the railroad bed, an accidental explosion of a charge he had set blew a 13-pound tamping iron straight through Gage's head, landing many yards away. Before the accident, Gage was said to be calm and mild mannered. After the accident, friends of Gage reported that he appeared to be mostly angry. This change stemmed from the damage caused to his frontal lobe and limbic system, which is the part of the brain involved in behavioral and emotional responses. Gage's case is a well-known example of how a traumatic brain injury (TBI) can cause personality changes. It's also one of the earliest and best-recorded cases of someone surviving a TBI. 
3. Know the saga of Patient HM. The study of HM showed that the hippocampus has an important role to play in memory, this is due to HM having his hippocampus removed and as a result he could no longer make new ltms which shows the hippocampus plays a role in moving info from stm to ltm. The famous case of H . M . demonstrated amnesia, a condition in which a person can remember previously encoded memories but cannot encode new ones.
4. Learn the roles of Wernicke’s and Broca’s areas and the deficits that result from damage to each. Wernicke's area is primarily responsible for language comprehension, meaning it helps us understand spoken and written language, while Broca's area is responsible for speech production, allowing us to articulate words and form sentences; damage to Wernicke's area leads to difficulty understanding language (receptive aphasia), while damage to Broca's area results in difficulty speaking fluently (expressive aphasia)