Behavioral Neuroscience II
Professor Wayne Sossin
Week 1, Class 1: Introduction
• Neurobiology of Goal‐Directed Behavior and Motivation
o Organising behavior to direct
• Neurobiology of Learning and Memory
Brain Circuitry: The brain is organized to permit goal‐directed behavior
• The brain evolved
o The goals that the brain was designed to reach are the goals that evolution selected
Survival: Homeostasis (Food, Water)
Safety: (Not getting killed)
Reprodution: Sex, Parenting (not getting your offspring killed)
The Brain is Plastic: The brain evolved to succeed within a changing environment
• Reward: Must be a mechanism to know when behaviors are successful.
o Reward must be coded for positive reinforcement.
• Negative Reinforcement: Must be a mechanism to know when behaviors are not successful.
• Memory: The brain must remember what was successful and what was not.
o The brain must predict what is going to happen in the future based on what
happened in the past.
Organisation of the Brain:
• Sensory Input (5 senses; internal states)
• Motor Output
• The stuff in between to decide what behavior to do based on:
o Sensory Input
o Internal states (Hunger, Injury, Pain, etc.)
o Goals (often competing goals)
The Brain is organized around chemical neurotransmission.
o Slow transmitters (dopamine, serotonin, noradrenaline, acetylcholine) and
o Neuropeptides (over 100)
Help to signal reward, state of system.
‐ Brain states are mainly mediated by slow, chemical synapses. Not electrical ones.
• Sensory motor‐circuitry:
o Fast transmitters (glutamate, GABA, glycine)
Make the sensory‐motor circuitry function.
• The human brain contains an estimated 100 billion neurons and a trillion glia.
o Inly less than 1% are involved in slow neurotransmission
• In an average person, it weighs between 1250 and 1450.
o About 2 to 3% of a person’s total body weight.
o It is an extremely active body part, receiving 15% of the heart’s output and using
about 20% of the body’s oxygen and glucose.
o Half of the roughly 30,000 human genes are expressed exclusively in the brain, and
70% of the other half are expressed both in the brain and periphery.
• Tools for studying the brain and its relation to behavior.
o Animal studies:
In vivo microdialysis and voltammetry
o Human studies:
Neuroimaging: PET, fMRI, aMRI, EEG
Post‐mortem tissue studies
Cerebrospinal fluid (CSF) studies
Monoamine synthesis inhibition
• Slow Neurotransmission:
• Cell bodies are located in Midbrain:
o Ganglia in Midbrain release:
• Ventral Tegmentum Area (VTA) and substantia nigra (SN)
• Raphe nucleus, mostly medial and dorsal raphe
• Pons, medulla and thalamus, but most important ones in locus
coeruleus in dorsal pons
• Septal nucleus, Mesopontine tegmentum area, nucleus absilis
o Forms an integral part of the brain
o Important for homeostasis through the release of peptides.
o Controls body temperature, hunger, thirst and circadian rhythms.
o Plays an important role in linking the nervous system to the endocrine system.
o Neuropeptide‐releasing neurons mainly in hypothalamus.
o Also involved in sexual Behavior.
• Stratium & Amygdala
o The striatum and the amygdala are both important in the attribution of motivational
value to stimuli.
Amygdala: Gives emotional value to previously neutral stimuli through the
process of Pavlovian conditioning.
Ex : Fear.
• Frontal Cortex :
o Higher level Motivation
Inputs come in, get sensed by certain
regions, and converge on other regions.
Overall, one interpretation is the following:
• Motivationally relevant stimuli (+ve & ‐ve) activate the amygdala
‐ Greater activity signals greater stimulus intensity.
• Current response is adequate:
‐ Central nucleus of the amygdala (CeN) and cortex facilitate sustained tonic dopamine
(DA) cell firing and release.
‐ Occurs via connections to the ventral tegmental area (VTA) and nucleus
accumbens (NAcc) / striatum
• Current behavioral response needs to be changed:
‐ Basolateral amygdala (BLA,) ventral subiculum of the hippocampus (vSub) and cortex
facilitate phasic increases in DA cell firing and provide additional sensory, affective,
and cognitive (executive) input.
Note: Norm White’s lesion work suggests that:
1) Stimulus ‐ response associations involve the dorsal striatum;
2) Stimulus ‐ reward associations: lateral amygdala and NAcc;
3) Shift in direction: hippocampus and NAcc
Neurocentric view of Behavior
• Neurons are the cells of the brain that are designed for information processing.
– Glia act mainly to support neuronal function
• Astrocytes support blood‐flow regulation, energy regulation, uptake of
• Oligodendroyctes myelinate axons to speed neurotransmission.
• Microglia are the immune cells of the brain and are important in dealing with
injury and infection.
• Understanding how the brain works requires understanding how neurons work.
• A cell designed for information processing
• Specializations for input, integration, and output
• Contains all compartments that other cells do
• ( gene expression, protein synthesis, degradation, etc. also occur )
“Computer Science” outline of a neuron.
Many dendrites: Neurotransmitter receptors
‐ Many inputs lead to cell body.
Cell body: Translation, Transcription, etc.
Single axon: One major output.
Axon Hillock: Integration center.
To fire or not to fire? All‐or‐nothing way.
Specializations for Input
• Dendrites receive information (they are the post‐synaptic part of the cell)
• Contain receptors for neurotransmitters released from the pre‐synaptic part of the cell
• Each neuron can receive input from many different sources.
• Integration is done by ion channels!
Specialization for integration Note: Neurons often named by
• Many ion channels regulate integration of incoming
the neurotransmitter they
• Many ion channels regulate the electrical level of the cell
Ex: Serotonergic release
• Axon hillock senses overall signal to determine if and serotonin.
when an action potential will go out
Specialization for Output
• Axon is specialized for speed of transmission (myelin, nodes of Ranvier, size)
• At presynaptic terminal, electrical signals are transformed into chemical signals
• Specialization for release of chemical signals at presynaptic terminal.
• Neurons have limited outputs compared to inputs (I.e. can sense many different
neurotransmitters, but release only a few).
• Major feature of brain plasticity is to modulate the strength of the connection between two
neurons (synaptic strength).
• To understand this, must understand synaptic communication.
– Release of neurotransmitter from presynaptic terminal
– Reception of neurotransmitter from postsynaptic terminal.
Fast vs Slow Neurotransmission
Fast neurotransmission: Slow neurotransmission
Neurotransmitter binds to a ligand‐ Neurotransmitter binds to a G protein coupled receptor
gated ion channel that then acts that can have many actions, including slowly altering the
directly to alter the voltage of the voltage of the post‐synaptic terminal.
(make ions move) (use metabolic pathways)
Neurotransmitter directly binds to Neurotransmitter directly binds to metabotropic receptors.
ionotropic receptors. ‐ Metabotropic receptors close to G protein.
‐ Produces a fast short lived ‐ Neurotransmitter binds receptor
electrical signal. Or indirectly ‐ Receptor activates a G protein in membrane.
by binding to metabotropic ‐ Active G protein activates an enzyme
receptors. ‐ Enzyme stimulates the production of a second
o (ex: cyclic AMP).
‐ These second messengers can then lead to changes
in the ion channel or induce a series of biochemical
reactions that produce long term changes in the cell
Slow, varied responses. Longer lasting.
At a given point of time, most neurotransmitters are located in the synaptic vesicles.
Organized at the active zone for rapid release.
Neuropeptides are not stored in synaptic vesicles. They only do slow neurotransmission, they do not
go through the Active zone.
Synaptic vesicles may be involved in slow neurotransmission as well as fast.
Four types of neurotransmitters
• Transmitters (synaptic vesicles) that use fast (or fast+slow) neurotransmission.
• Transmitters (synaptic vesicles) that use slow neurotransmission.
• Peptide Transmitters (dense cored vesicles) that use slow neurotransmission
• Other transmitters that are not in synaptic or dense cored vesicles
– Nitric Oxide (How neurons control blood vessels);
– Anandamide (ligand for the cannabinoid receptor)
• Neurons use only one transmitter
• While generally true and a useful concept, several caveats and modifications
– True mainly for transmitters in synaptic vesicles.
– Both peptide transmitters and non‐vesicular transmitters are often present at same
terminal as synaptic vesicles.
– Exceptions to the rule:
• A glutamate transporter is found in some cells with other classical
transmitters; e.g. GABA, dopamine and 5‐HT; in some cases this leads to co‐
release of two distinct transmitters.
Timing of Fast neurotransmission
• Pre‐synaptic action potential opens calcium channels (0.3 ms)
• Calcium enters and causes synaptic vesicles to fuse (0.5 ms)
o Longer, more complicated step
• Neurotransmitters go across the cleft, bind receptors (0.4 ms)
• Receptors open, ions flow in, Action potential caused (0.1 ms)
1.3 ms, fast process.
Fast speed of release
• The time between calcium entry and vesicle fusion is very fast (0.5 msec)
• Calcium sensor on synaptic vesicle (synaptotagmin)
• Plasma membrane SNARE proteins.
What does a neuron need to use a neurotransmitter?
– A vesicular transporter to concentrate the transmitter into a vesicle
• Neurotransmitter must be loaded into vesicle
– Biosynthetic enzymes to synthesize the neurotransmitter
• Acetylcholine and Dopamine are not usually present in all cells
• Only found in cells with appropriate enzymes
• (glutamate and glycine are not specifically synthesized in cells that use
– Uptake transporters in plasma membrane
• If this isn’t present, another mechanism must be present to inactivate signal:
– A mechanism for degradation of the neurotransmitter
***Botulinum and tetanus toxins most often used***
Diagram of a presynaptic terminal
• Energy is needed to load a vesicle.
• ATP used to create gradient.
• Vesicular transporter uses gradient to load
serotonin from cytoplasm to synaptic vesicle.
Plasma Membrane Transporter
• Loads serotonin into the cell
• Uses permanent sodium gradient
– Major excitatory neurotransmitter
– Brain plasticity mainly involves glutamate synapses
– Not specifically made in glutaminergic cells
• (Cells that use glutamate as their major neurotransmitter)
• Present in every cell
– The critical protein that determine the use of glutatame is the transporter
• Moves glutamate from the cytoplasm to the vesicle
• (Glutamate vesicular transporter or GluVT).
• Gamma‐Aminobutyric acid (GABA)
– Major inhibitory neurotransmitter
– When GABA released, opens ligand‐gated chloride channel
• Depolarizes the cell
• Prevents action potential firing.
– Made by enzyme (Glutamic‐Acid decarboxylase; GAD) only in cells that use GABA as a
– Inhibitory transmitter made in spinal cord
– Like glutamate, glycine is found in every cell.
• Blocking glycine receptors leads to death
• Acetylcholine (ACh)
– Made in all motor neurons and released onto muscle cells.
• Every neuromuscular junction is a cholinergic synapse.
• Muscle has a nicotinic acetylcholine receptor.
– Made in specific neurons only
• Made by enzyme Choline‐Acetyl transferase (ChAT).
Mechanisms are needed to rapidly end fast neurotransmission.
• Need to distinguish actions of each action potential (rate‐code), so need to end fast
– Receptors desensitize rapidly
• Receptor inactivates and won’t open again until ligand leaves.
– Astrocytes take up GABA and Glutamate with specific transporters.
• Astrocytes completely surround synapse to capture neurotransmitters using
– Acetylcholine is degraded by an extracellular enzyme
• Specific to Acetylcholine, neurotransmitters don’t all work the same way.
***Receptors decide whether a signal is slow or fast. Not the sending cell***
– Synthesis is the as in motor neurons.
– Can distinguish receptors:
• Nicotine works by acting as acetylcholine in ionotropic receptors.
• Muscarine works on metabotropic (muscarinic) receptors.
– In brain, nicotinic receptors are not involved in fast neurotransmission:
• Present on presynaptic terminals (especially on dopaminergic neurons)
• Do not act metabotropic receptors
• Regulate transmitter release (similar to slow neurotransmission). • Dopamine
– Two enzymes involved in synthesis:
Tyrosine Æ L‐Dopa Æ Dopamine
• Not specific to dopaminergic neurons.
• Also present in cells that make noradrenaline (norepinephrine) and adrenaline
– Distinct dopamine receptors have distinct functions (e.g. D1 vs D2 receptors)
• D1 activate cAMP pathway
• D2 activate pathway to get rid of cAMP.
Receptor determines the ligand’s action.
• Pharmacological agents can distinguish between these two targets of
Tyrosine is an amino acid that is converted
We can get tyrosine from our diet and also
make it in the liver from phenylalanine. We
cannot make our own phenylalanine,
though, and have to obtain it from our diet.
Tyrosine hydroxylase (TH) is the rate limiting
enzyme in DA synthesis.
Parkinsons: L‐DOPA diminishes symptoms.
Allows more Dopamine to be made, sicnce L‐
DOPA creation is the rate‐determining step.
Terminating the Action of DA
• Rate of termination should be carefully
o Modulating degradation/reuptake
allows for a finer control.
• DA levels are controlled and metabolized
within and outside the cell.
MAO controls levels of monoamines in the cell.
• MAO converts DA to an inactive
o It’s found in the monoaminergic
o MAO inhibitors (Ex: deprenyl)
prevent the destruction of DA.
o More DA is released when an
action potential reaches the
o Serve as a DA agonist. Catechol‐O‐methyltransferase (COMT) breaks down extracellular DA.
• Plays a bigger role
DA (not catabolized) diffuses in the synapse.
• Can be taken back up into the neuron by DA transporters.
• Cocaine and methylphenidate block DATs.
o More DA remains in the synaptic cleft.
o Continues neurotransmission and stimulate post synaptic receptors.
Autoreceptors also regulate DA levels.
• Found in the dendrites, soma and terminal buttons of dopaminergic neurons.
• Activation of autoreceptors on in the dendritic and somatic membrane decreases neural
o Occurs by hyperpolarization.
o Also suppress tyrosine hydroxylase activity.
Decreases the production of DA.
• DA, like other monamine act through G‐coupled receptor proteins.
• D1 and D2 receptors are both metabotropic.
o D1 are exclusively postsynaptic
Stimulation increases the production of cyclic AMP (second messenger)
o D2 receptors are both pre and post synaptic.
D2 receptors decrease cAMP production.
Stimulation of D3 and D4 also acts this way.