Molecular Neurobiology Exam 1

What did Ramón y Cajal contribute to neuroscience?

early pioneer who used observations of nervous tissue to develop early evidence for the neuron doctrine

What was the old idea about nervous tissue before the neuron doctrine?

Nervous tissue was thought to be like a gland, secreting chemicals or fluids that were then passed to the body.

What did Golgi develop that helped Cajal study neurons?

Golgi developed a silver stain, which Cajal applied to nervous tissue to visualize neurons.

What is the brainstem?

The oldest part of the brain, where the spinal cord swells as it enters the skull. It is in charge of many automatic survival functions

What are the three major regions of the brainstem?

Midbrain, pons, and medulla

What are some functions associated with the midbrain?

It is involved in motor movement, especially functions involving the eyes and auditory/visual processing

What is the medulla?

Controls involuntary functions that occur without conscious thought, including many vital functions such as breathing and BP (damage can therefore be extremely difficult to survive)

What is the pons?

Part of the hindbrain and acts as a bridge, containing nerve fibers that connect different brain regions, including the cerebellum and medulla.

What does the pons relay?

It relays signals from the cerebrum to the cerebellum and medulla, and helps relay information onward toward the thalamus

Structures and function of the hindbrain?

• medulla, pons, and cerebellum

• mainly controls breathing and movement

What is the reticular formation?

nerve network in the brainstem that controls arousal; yawning can encourage wakefulness

What does the cerebellum coordinate?

hearing and balance, and more broadly for movement coordination and balance

How is the cerebellum divided?

divided into two hemispheres, with each hemisphere controlling the corresponding side of the body for cerebellar coordination

What is Friedreich's ataxia? (Frataxin)

Friedreich's ataxia is a hereditary disease that primarily targets the cerebellum and causes neurological problems involving muscle weakness, loss of balance, and loss of coordination (ataxia)

What may frataxin do, and what happens when its missing/defective?

Frataxin may regulate iron inside the mitochondria and is theorized to act as a storage depot for iron, releasing it only when needed

- if defective: free iron accumulates in mitochondria, which can cause oxidative stress (free radicals)

What is the cerebral cortex?

wrinkled gray matter covering the cerebral hemispheres

What is the frontal lobe involved in?

The frontal lobe is involved in judgment and planning future action

What is the parietal lobe involved in?

The parietal lobe is involved with somatic sensations (touch)

What is the primary function of the occipital lobe?

The primary function of the occipital lobe is processing visual information

What is the primary function of the temporal lobe?

primarily involved in hearing and memory

Contralateral organization of cerebral hemisphere

cerebral hemisphere controls sensory and motor processes on the opposite side of the body

What is the corpus callosum?

large bundle of nerve fibers that allows the left and right cerebral hemispheres to communicate

What is aphasia?

language and communication disorder that affects your ability to speak, write, and understand verbal or written words

What happens if Broca's area is damaged?

• impaired speaking/speech production

• Broca = talking

What happens if Wernicke's area is damaged?

• impaired understanding/interpreting language

• Wernicke’s = understanding

What is an electroencephalogram (EEG)?

amplified recording of the electrical waves sweeping across the brain's surface, measured by electrodes placed on the scalp

positron emission tomography (PET) scan

visual display of brain activity that detects a radioactive form of glucose while the brain performs a given task

magnetic resonance imaging (MRI)

magnetic fields and radio waves to produce computer-generated images that distinguish different types of brain tissue

functional magnetic resonance imaging (fMRI)

detects changes related to blood carrying oxygen or blood without oxygen and how blood moves around the brain; allows researchers to see which brain regions become active during different tasks

- Detection of deception can have about 90% accuracy

What are microglia?

Microglia are phagocytes that are mobilized after injury, infection, or disease

What are the three types of macroglia?

oligodendrocytes (CNS), schwann cells (PNS), astrocytes (CNS)

What do oligodendrocytes and Schwann cells have in common?

Oligodendrocytes and Schwann cells form myelin, which helps insulate nerve cell axons

Functions of astrocytes?

• buffer excess K⁺ in the extracellular space, help maintain proper extracellular K+ concentration around neurons

• End-feet are extensions that surround blood vessels to help form BBB

What is the blood-brain barrier (BBB)?

protective barrier formed by tight junctions associated with blood vessels and astrocyte end-feet, which helps prevent many substances in the blood from entering the brain’s nervous tissue

What are the 3 functions of the BBB?

1. Protects the brain from foreign substances in the blood that may injure the brain

2. Protects the brain from hormones and neurotransmitters in the rest of the body

3. Maintains a constant environment for the brain

What is the thalamus responsible for?

brain's sensory switchboard; directs messages to the sensory areas in the cortex and transmits replies to other brain regions, including the cerebellum and medulla

• process and relay ALL sensory information from the body to the cerebral cortex (exception of olfactory)

Morphology of neurons

• Cell body (soma)

• Dendrites (input region)

• Axon (output region)

• Presynaptic terminal

Dendritic spines are…

tiny protrusions on dendrites that host majority of excitatory synapses of the brain

Disruption of dendritic spines cause?

PKU, down syndrome, fetal alc, asphyxia

Action potentials (AP)

Rapid, transient, all-or-none nerve impulses that have an amplitude of 100 mV over 1 msec

Where are action potentials initiated?

axon hillock

how is information conveyed by an AP interpreted and analyzed by the brain if they all have the same shape and size?

frequency coding

Myelin

fatty insulated sheath that increases speed of AP

monosynaptic reflex system

direct connection between sensory and motor neuron, faster than contacting the brain

Afferent neruon’s (sensory)

specialized cells to detect stimuli, start in PNS and travels to CNS - deliver sensory information

- ex. sense stretch of muscle

efferent neurons (motor)

neurons that take information from the brain to the rest of the body; leaving spinal cord

Interneurons

neurons within the brain and spinal cord that communicate internally and intervene between the sensory inputs and motor outputs (can inhibit)

signaling nerve cells (4 diff signals)

1. local input signal

2. trigger (integrative)

3. long range conducting signal

4. output (secretory) signal

Resting Membrane Potential (RMP)

-65 to -70 mV; K+ leak channels are open leaving behind neg charge and making inside more neg than outside

differential in electrical potential (2 factors):

• unequal distribution of charged ions on either side of membrane

• selective permeability to K+

concentration gradient vs electrical gradient (both work together)

• C.G: ions diffuse down conc. gradient (high to low)

• E.G: ions move towards regions of opp. elec. charge

stretch reflex (5 components of unipolar nerve)

muscle contraction in response to stretching within the muscle (knee-jerk)

1. receptor

2. sensory neuron

3. integration center

4. motor neuron

5. effector

muscle stretch (spinal cord):

- exciting: the same muscle to contract

- inhibiting: opposing muscle (inhibition)

- damping: original stretch and maintain stability

ion channels

A transmembrane protein channel that allows a specific ion to diffuse across the membrane down conc. or elec. gradient

local signal

spreads passively along axon, but must be amplified to generate an AP

seq. of signals that produces a reflex

A. receptor (synaptic) potential: depolarization

B. trigger action: reach threshold

C. AP: all-or-none spikes in axon

D. output signal: transmitter released

local (passive) and propagated signals

• local (passive): occur at the site of stimulation; decrease in amplitude with distance

• propagated signals: travel along the length of the axon w/o loss of amplitude

Local (passive) signals

- small amplitude

- graded summation

- decrease with distance

- can be hyper or depolarizing

Propagated (active signal)

- large amplitude

- all or none

- do not decrease with distance

- always depolarizing

Phenylketonuria (PKU)

sever cognitive fxn. from defective recessive gene that prevents metabolism of phenylalanine hydroxylase (PAH enzyme that converts AA Phe to Tyr)

- lack both functional copies build up high phenylalanine (rr)

- high levels of Phe lead to toxic metabolite that interferes with normal maturation of the brain

- treatment: restrict protein intake

Behavior is shaped by both...

gene and environment interactions, but strength can vary on situation;

• PKU ex. both heredity and environmental factors in the diet are clearly necessary for the expression of this form of mental deficiency

concordant studies

the tendency of twins to carry the same trait or disorder

- value 1 = trait is 100% due to genetics (blood type)

obesity -causing mutation on chromosome 6 led to identification of ob gene (influences eating behavior)

ob gene encodes leptin protein, selectively expressed in adipose tissue and released into the bloodstream (when adipose tissue decreases, leptin levels decrease and animal eats more)

- genes can be more isolated in animals

(functional leptin=skinny)

B2-DRD4 (dopamine receptor subtype 4) gene and cheating

dopamine is linked to self control and risk taking, ppl with DRD4-7R+ variant have lower dopamine sensitivity making them more likely to cheat/ riskier behavior

• DRD4-7R+ = need more dopamine to feel good

vasopressin (social bonding)

neuropeptide involved in pair bonding and parental behavior

- prairie voles: form long-term pair bonds and help raise offspring (monogamy)

- high expression in ventral pallidum (reward region)

HD is a autosomal dominant disorder characterized by 4 features

• heritability

• chorea: rapid movement (to dance)

• cognitive impairment

• death of neurons in caudate nucleus (basal ganglia)

occurs in 4th-5th decade of life

HD is highly penetrant (chromosome 4)

codon (CAG) encodes glutamine, 48 or more repeats cause HD

HD successive generations

mutant gene manifests at greater severity (earlier age) with each generation (anticipation)

Fragile X Syndrome

injury to gene on the X chromosome, producing mild to moderate mental retardation

• affects females (similar to down syndrome)

• creates toxic function w/ expanded polyQ (glutamine)

as of 202 there were more than 40 known ______ _______ disorders affecting diff parts of the body

repeat expansion

Tominersen lowers mutant huntington (MHTT)

but does not show meaningful slowing of Huntingtons disease progression

Dr. Nancy Wexler

• 1 in 10 ppl HD at lake maracaibo

  • Norm: <31 CAG

  • Grey: 32-38 CAG

  • HD: > 38 CAG

• more CAG = more GIN = greater toxicity

Why do ions rarely cross phospholipid membranes even though they diffuse freely in aqueous solution?

Ions are strongly attracted to water molecules and are surrounded by water, making it difficult for them to enter the membrane’s hydrophobic interior

Why are ions strongly attracted to water molecules?

Water molecules are dipolar

- water has a net charge of zero, charge is separated within the molecule because of the unequal sharing of electrons between oxygen and hydrogen.

- Neighboring water molecules form weak H bonds, but relatively strong when combined

Why can ions and other molecules dissolve in water?

Their ability to dissolve in water is due to water's polarity, water molecules interact with ions through electrostatic forces

What is a water shell?

layer of water molecules that surrounds an ion in solution. For example, Na⁺ is surrounded by water molecules

What are hydration energies?

energy gained by transferring an ion from a vacuum into an aq solution. Small ions generally interact more strongly with water and have greater hydration energies than large ions.

How does ion size affect its interaction with water?

Small ions interact more strongly with water than large ions. Water molecules can approach the center of charge more closely around a small ion, producing a stronger electrostatic force.

What is Coulomb's law and how does it apply to ions?

Coulomb's law states that electrostatic force is proportional to the inverse square of the distance between charges.

Force = 1/2x

- closer the charges are, the stronger the force

How do large and small ions differ in shedding their water molecules?

Larger ions, such as Cs⁺, can shed their associated water molecules more easily and rapidly than smaller ions such as Li⁺

Why is ion size important for ion channels?

Differences in how strongly ions interact with water have important consequences for the ion selectivity of channels—ion channels can selectively allow certain ions to pass

lipid bilayer (membrane)

• inside = hydrophobic

• outside= hydrophilic

Why do ions have difficulty crossing lipid bilayers?

The inside of the lipid bilayer is hydrophobic, so it strongly resists charged ions

Why is moving an ion through the hydrophobic membrane energetically unfavorable?

The ion must either drag water into the hydrophobic region or shed the water molecules surrounding

How much more likely is an ion to remain in water than a hydrocarbon environment?

10⁷² more likely to remain in an aq environment

How do ions cross lipid membranes?

Through specialized pores/channels or carriers that provide an environment favorable to ion movement

What are the two types of molecules that increase ion movement?

Carriers and pores

What does a carrier do?

Binds the ion → changes shape → opens to the opposite side → releases the ion

What is a pore?

A water-filled channel through the membrane that allows ions to pass without the protein changing shape

What is the main difference between carriers and pores?

→ Carriers: bind ions + change shape

→ Pores: continuous/open channel + no shape change

What are the polar and non-polar regions of these proteins used for?

Polar groups face/interact with the ion; non-polar groups interact with the lipid membrane

What is valinomycin?

A carrier that specifically increases membrane permeability to K⁺

What is gramicidin?

A pore that allows small cations, but not anions, to cross the membrane

Are carriers or pores specific

- Carriers: highly specific and can become saturated

- Pores: less selective and have high throughput/capacity

Importance of a carrier vs. a pore

both solve the same problem: ions cannot easily cross the hydrophobic lipid bilayer on their own

Carrier = carries the ion

Pore = provides a passage for the ion (faster)

What determines the direction of ion flow through a pore?

Ion concentration gradient + electrical potential across the membrane

What do pores change, and what do they NOT change?

Pores increase the rate of ion flow, but do not determine its direction

How do pores increase the rate of ion movement?

They lower the energy barrier (activation energy) for ions crossing the membrane

Why are ion pores compared to enzymes?

Both lower activation energy without changing the initial or final energy states (ΔG)