NSCI Units 1-6

Basal Forebrain Complex

• Acetylcholine diffuse modulatory system

• The Medial Septal Nuclei AND the Basal Nucleus of Meynert

• Learning and memory

Pontomesencephalotegmental Complex

• Acetylcholine diffuse modulatory system

• Responsible for sleep/wake cycles

Neuromuscular Junction

• Acetylcholine modulatory system

• Contains ionotropic Nicotinic Receptors

• Depolarization causes muscle contractions

Choline acetyltransferace (ChAT)

Enzyme that catalyzes ACh synthesis

Vesicular acetylcholine transporter (VAChT)

Transporter that moves ACh into vesicles

Choline transporter (CHT)

Transporter for bringing choline into the cell for ACh synthesis

Acetylcholinesterase (AChE)

Degradation enzyme that breaks down acetylcholine in the synapse

vGluT1 and vGluT2

Glutamate transporters

GAT

GABA transporter

GAD

Enzyme that synthesizes GABA

DBH

Enzyme that synthesizes NE

Dopamine Transporter (DAT)

Protein on pre-synaptic neuron that removes dopamine from the synapse

Serotonin transport protein (SERT)

• Transporter that brings unused serotonin back into the neuron

• Targeted my MDMA and put into reverse, causing neurons to release large amounts of serotonin

  • Overtime causes sharp decrease of SERT and 5-HT in the brain

Tryptophan Hydoxylase (TPH2)

Enzyme that synthesizes tryptophan into serotonin

Monoamine Oxidase (MAO)

Enzyme that breaks down excess serotonin, dopamine, and norepinephrine from synapse after reuptake

Nicotinic Receptors

• Ionotropic ACh receptor

• Found in skeletal muscles, neuromuscular junction

• Allows flow of Na⁺ and K⁺, but more permeable to Na⁺ which aids in depolarization

Muscarinic Receptor

• Metabotropic ACh receptor

• Can inhibit or excite neuron, depending on subtype

AMPA

• Glutamate ionotropic receptor

• Allows large influx of Na⁺

• Very quick excitatory action

NMDA

• Glutamate ionotropic receptor

• Requires glutamate binding AND membrane depolarization to open, blocked by Mg⁺⁺ ions

• Allows influx of Na⁺ and Ca⁺⁺

• Influx of calcium aids in reinforcing the synapse through internal signals

• CRITICAL FOR LEARNING AND MEMORY

mGluR

• Metabotropic glutamate receptor

• Slower, longer lasting excitatory action

GABA_a

• GABA ionotropic receptor

• Permeable to Cl^-, aiding inhibition of neurons

• Agonists are ethanol, benzos, barbituates, and neuro steroids

GABA_b

• GABA metabotropic receptor

• Slow, prolonged inhibitory action

Raphe Nuclei

• Serotonergic diffuse modulatory system

• Midbrain raphe to forebrain

• Brainstem raphe to spinal cord

• Sleep/wake cycles, mood, modulation of respiration

Locus Coeruleus

• Noradrenergic diffuse modulatory system

• Responsible for vigiliance, attention, and memory retrieval

Mesocorticolimbic Pathway

• Dopaminergic diffuse modulatory system

• Ventral Tegmental Area (VTA) to nucelus accumbens and cortex (specifically frontal lobe)

• Regulates reward, pleasure, and addiction

• Affected by acute drug exposure: VTA is stimulated and causes increased dopamine release in NA

Mesostriatal Pathway

• Dopaminergic diffuse modulatory system

• Substantia nigra to striatum

• Regulates volunatry motion

  • Parkinsons is caused by a loss of nerve cells in the substantia nigra, which make dopamine

Amino Acid NTs

Glutamate, GABA, Acetylcholine

Monoamine NTs

Dopamine, Serotonin, Norepinephrine

Tryptophan is a Precursor for…

Serotonin

Tyrosine is a Precursor for…

Dopamine, Norepinephrine

CB1 Receptor

• Purpose is to reduce calcium channel opening in pre-synaptic neuron, inhibiting NT release

• Most common metabotropic receptor in the CNS

• Receives endocannabinoid NT

Endocannabinoids

• Lipid molecule manufactured on demand for retrograde signaling

• Vigorous AP firing in the post-synaptic neuron causes influx of calcium, which stimulates synthesis of endocannbinoid molecule

Endocannabinoid = En domand (on demand)

THC

Partial agonist of CB1 receptor

• Binds with high affinity but low efficacy

• Suppresses NT release, causing pain relief, lower blood pressure, and decreased nausea

Hallucinogens

Alter sensory perception and produce unusual experiences

LSD (Acid)

Powerful agonist of 5-HT receptors in visual cortex

MDMA (Ecstacy)

• Stimulates visual cortical serotonin levels but also changes dopamine levels

• Reverses the serotonin transporter, causing excess serotonin to be dumped back into the synapse

Cocaine

• Stimulant that antagonizes (blocking) DAT and NET, causing immediate increase in NT in the synapse

• Overtime body tries to fix oversensitivity by decreasing number of receptors

  • Same effect from use of meth, alcohol, and heroin

Amphetamines

• Stimulants that causes NET and DAT to reverse and spill NE or DA back into the synaptic cleft

Allostatic Points

New baseline levels of homeostasis due to repeated drug exposure

• Abnormal set points

• Restricted range

• Brain may lose ability to restore normal homeostatic levels

Observation

A scientist creates an experiment and watches to see what happens

• Nerve fibers are cut and affect to motor control is measured

Repitition

An experiment is repeated with more subjects/participants to get more data

• Another round of rats go through an experiment

Interpretation

Depending on the scientist’s personal views and current information, data from an experiment is placed into context

Verification

Overtime, multiple different labs across many years repeat the experiment or versions of it, solidifying the findings further into the scientific diaspora

• Another lab in London repeats an experiement from Tokyo and gets similar results

• Consistency overtime

Molecular Neuroscience

• The smallest players on the inside of cells that work to keep the brain functioning

• Genes, proteins, enzymes, channels, neurotransmitters, receptors, transporters

• What is allowed into and out of a cell, activation of new neuron growth, intricacies of the synapse

“How is the cell doing this?”

Cellular Neuroscience

• Understanding what the cell as an “individual” is causing or doing

• How neurons are communicating (synapses), electrical signals

• Different subtypes, glia, non-neuronal cells

“What is the cell doing?”

Systems Neuroscience

• The circuitry of groups of neurons to create sensation and perception

• Visual system, auditory system

• Making decisions and executing movements

Behavioral Neuroscience

• How multiple circuits are involved in creating human behavior and mood

• Parts of the brain involved in sex, drugs, love, sleep

• Human interactions within group settings and individuals

Cognitive Neuroscience

• How the brain creates the mind

• Self-awareness, memory, language, imagination

Reticular Theory

• Golgi’s neuronal organization which thought that all neurons were physically connected like a web, spanning the brain and body

• Went against the cell doctrine (all cells are individual)

• Overtime proved to be incorrect

Neuron Doctrine

• Cajals theory of neuronal organization that proposed neurons as individual cells that communicate with each other

• Supported the cell doctrine

• Overtime proved to be correct

Replacement

Find alternatives to animals for experiments

• Use computer models

• Human volunteers

• Cell cultures

Reduction

If animals are necessary, minimize how many are used by improving techniques

• Improve experimental techniques

• Improve data analysis

• Share information with other researchers

Refinement

When animals are being used, make better experiments and tools so that animals suffer less

• Less invasive techniques

• Better living conditions

• Better medical care

Immunohistochemistry (IHC)

• Uses antibodies to bind and find a specific PROTEIN

• See where proteins are located in cells and tissues, like enzymes or transporters

In Situ Hybridization (ISH)

• Detects mRNA and RNA transcripts

• Complementary nucleic acid probe

• Finds where a particular gene is bring expressed

Ligand-binding method

• Finds specific receptors or binding sites

• Labeled ligand (e.g. radioactive)

• Shows recepter location and their density

Transcriptomics

• Measures many/all mRNA/RNA transcripts at one time

• Broad picture of what a cell is expressing

• Can help classify different cell types

Golgi Stains

• Stains a few neurons in their entirety

• Doesn’t stain non-neuronal cells

• Helped us understand neuron anatomy

Luxol Fast Blue

Myelin (white matter) blue

Nissl Stain

Stains cell bodies purple (gray matter)

Categorizing Neurons

• Gene expression

• Connections

• Structure

  • Number of neurites

  • Axon length

    • Golgi Type I: projection neurons (pyamidal)

    • Golgi Type II: local neurons (stellate)

• Function

• Anatomical location

• Excitatory/Inhibitory

Astrocytes

• Most common type of glial cell

• Form around synapses, help control excitatory/inhibitory

• Take up excess NT and release their own NT

Radial Cells

• Contribute to neurogenesis

• Make a scaffold for baby neurons to be implemented

Myelin

• Oligodentrocytes: Connect to multiple axons, found in the CNS

• Schwann Cells: Myelinate one sheath, found in the PNS

Ependymal Cells

Secretes cerebrospinal fluid into the brain

Satellite Cells

Helps regulate neuron environment in the PNS

Microglia

Cell immune support, helps get rid of decaying neurons, synaptic pruning

Hodgkin and Huxley

Discovered the ionic mechanisms behind how an AP is delivered, and understanding electrical transmission

How an AP Propagates

1. Na⁺ enters VG channels at the nodes of ranvier, creating an excess of positive charge inside the axon

2. Electrical current spreads out, since Na⁺ channels behind it are inactive, AP moves forwand not backward

3. Myelin keeps positive charge inside (less open channels)

4. Next node gets depolarized to threshold, new AP regenerates

Steps of VG Na⁺ Channels

1. Closed: Threshold not reached, channels are closed

2. Open: Threshold reached, channels open and Na⁺ depolarizes

3. Inactivated: Na⁺ channels close, absolute refractory period

Orthodromic

AP goes in one direction

Antridromic

AP goes backwards/either direction

Steps for Chemical Synaptic Transmission

1. NT are made in the cell and placed into vesicles

2. AP arrives to the axon terminal

3. Depolarization causes Ca⁺⁺ entry into the cell

4. Vesicles merge with the neuronal membrane

5. NT are released across the synaptic cleft and received into post-synaptic receptors

6. Signals are interpreted as EPSPs or IPSPs

7. NT still left in the synapse diffuse, get taken up by NT transporters, or are destroyed by enzymes

Steps for Vesicle Fusion

1. Ca⁺⁺ ions come into the cell

2. Ca⁺⁺ binds to synaptotagmin

3. Complexin protein is displaced

4. SNARE proteins unwind, pore opens and releases NT

Spatial Summation

When PSPs coming from multiple different axons around the same time are added together

Temporal Summation

When PSPs are sent from one axon in very close intervals. Closer together = stronger summation

Dendritic Length Constant

An index of how far depolarization will spread down an axon

• Higher constant = farther travel

• Not actually constant, variables are changing

Determinants of Conduction Velocity

• Axon diameter: bigger diameter means less internal resistance

• Myelination: increases membrane resistance

• Internode length: longer nodes mean faster propagation

• Temperature: heat helps APs travel fast

Resistance and DLC

• Lower internal resistance is better

  • Thin dendrites have small DLC

• Higher membrane resistance is better

  • Leaky dendrites have small DLC

Shunting Inhibition

When a specific synapse on the axon sends an IPSP that stops an AP from propagating fully down the axon

Membrane Potential

Maintained by the transporter pump (3 Na⁺ out, 2 K⁺)

Steps to an AP

1. Resting potential: all VG channels closed

2. Threshold: EPSPs bring membrane potential to threshold, VG Na⁺ channels open, VG K⁺ channels activate but don’t open

3. Rising phase: Large amounts of Na⁺ flood the cell

4. Overshoot: After 1ms, VG Na⁺ channels close and VG K⁺ channels open

5. Falling: Large efflux of K⁺ repolarizes the cell

6. Undershoot: K⁺ leaves the cell past RMP, causing hyperpolarization

Absolute Refractory

Period in which VG Na⁺ are inactivated, and physically impossible to generate new AP

Relative Refractory

Period after the absolute refractory where VG Na⁺ channels are active again, but VG K⁺ channels remain open, causing membrane potential to be lower than normal. Takes stronger depolarization to reach threshold

Sodium Channel

• 4 domains of 6 alpha helices come together

• S4 has charged amino acids which allow it to response to changes in membrane voltage

• S5-S6 form the pore loop

• 3 states: Closed, Open, Inactivated

Primary Sensory Neuron

• Help detect sensations

• Sends information to the CNS

• Have special dendrites that allow APs to occur

• Often unipolar

Interneurons

• Only form connections with other neurons

• Bridges sensory and motor neurons

• Only found in the CNS

Motor neurons

• Form synapses at muscle cells and cause movement

• Receive information from the CNS

Divergence

• One neurotransmitter can activate many different receptors, leading to different physiological effects

  • ONE to MANY

• E.g. a small number of locus coelus neurons send signals across the brain

Convergence

• Many neurons send information to one system

• Multiple neurotransmitters come together to influence one effector system/physiological reaction

  • MANY to ONE

Dopamine - Unexpected Reward

Cue sounds and unexpected reward given

• Surge of dopamine followed by return to baseline

Dopamine - Expected Reward

Cue sounds and reward is given

• Surge of dopamine comes at cue sound, then returns to baseline

Dopamine - Negative Prediction Error I

Cue sounds but reward is not the expected stimulus

• Dopamine surges at cue sound, but lack of reward causes dip below baseline

Dopamine - Negative Prediction Error II

No cue sounds, but patterned routine causes dopamine surge at the anticipation, followed by dip below baseline due to no stimulus