Conditioning and Learning Lecture

learning vs memory vs conditioning

L: acquire new/modify existing knowledge

M: encode, store, retrieve, and retention of info

C: learning process by association w stimuli in the environment

BRAIN SUBDIVISIONS: CNS vs PNS

cns- brain spinal cord

—tracts/pathways, collection of axons + nuclei collection of cells

glia cells= astrocytes, microglia, oligodendrocytes

pns- ganglion, nerves (nerves connect w sensory

receptiors and w muscles to engage environment)

—ganglia cells, nerves axons

glia cells= schwann cells

subdivisions cont. forebrain, midbrain, hindbrain, cortex

forebrain: cerebrum( surface = cerebral cortex), thalamus, hypothalamus

midbrain: tectum

hindbrain: pons, medulla ob., cerebellum

cerebral cortex

sulci= grooves deeper tissue in brain, animals have much less surface therefore less ridges

cerebral cortex= gray matter

white matter= cell dense, lipid rich, white

cells: neuron what they do, send…

receive/process info, generate signals (APS) propagated along circuit

-glia provide support functions, outnumber neurons 10:1

NEURON MORPHOLOGY

dendrites: extensions of cell body, receive thousands of synaptic inputs, have a spine membranous extusion that protrudes from dendrite, spines can be different shapes/change/communicate

—spine density in cerebral cortex increases in early development, max density from 2-8 yrs old, due to synaptogenesis, though to facilitate learning

NM cont. dendrites

after spines peak, density declines between 8-18 yrs old due to synaptic pruning. sensorimotor cortex highly dense, declines, PFC less dense becomes dense later in life

Dendritic spines LTM: synaptic changes in adult for memory

LTM= increase in number/size of spines within hours of mem formation, hippocampus dndrite

Autism Spec Dis.= reduced synaptic pruning, hyperconnectivity

Schizophrenia= excessive pruning/ particularly in adolescence

NM cont, soma

metabolic center, contains nucleus, stores genetic material and organelles

-DO NOT HAVE CENTRIOLES, essential for cell division, making replication impossible

Endoplasmic Reticulum synthesizes proteins/ ribosomes/ phospholipids

Golgi App packages proteins/phospholipids into vesicles

MITCHOCHONDRIA: breakdown of nutrient for energy, prod ATP, brain consumes 20% of energy

lysosomes break down waste

cytoplasm suspension that fills out cells membrane

NM axon

conducts APs to transmit info, and molecules/organelles between soma and axon

-no protein synthesis on axon, ribosomes present in presynaptic cells

-AXON HILLOCK, ap is generated, high density of voltage gated channels than rest of neuron

-microtubules, organize as highway to transport materials, form part of cells skeleton/shape

transport from soma to terminals= anterograde, protein example: kinesin

terminals to soma, waste taken to be broke down= retrograde, dynein

ACTION POT: myelin sheath: schwann cells in PNS

oligodendrocytes (CNS)

axon initial segment, myelin, node of ranvier, heminode, syn. terms.

types of cells: pyramidal cell, retinal bipolar cell,cerebellar purkinje cell

types of cells cont: based on prolongations from soma + axon projections + effect of neurons

SOMA: bipolar, unipolar, multipolar

—all 3 vertebrates-

bipolar and unipolar invertebrates, in spinal cord, brainstem etc

AXON types: projection/principal neuron= long axons that project to another region

local/interneuron= short axons that ramify within a given region

excitatory= be projection or local, use glutatmate as NT

inhibitory= local interneurons, GABA as NT

AXON terminal region: synaptic boutons

-at its end, axon divides w specialized endings = syn boutons

-SB from single neuron can make synaptic connections w many other neurons

SB IS MAIN TRANSMITTING ELEMENT OF NEURONS, RELEASE NT

Synapses: chemical vs electrical

chemical= info transported chemical via NT

—voltage gates Ca channel, NT molecules, etc

electrical= info transmitted via direct ion flow between neurons

synaptic transmission: ap arrives in presyn. axon term= NT molecules released from vescles into synaptic cleft, they bind to specific receptors= electrical signal in post syn cell

transmission steps

Action potential arrives at the presynaptic terminal
↓
2. Voltage-gated Ca²⁺ channels open
↓
3. Ca²⁺ enters the presynaptic terminal
↓
4. Synaptic vesicles fuse with the membrane
↓
5. Neurotransmitter is released into the synaptic cleft
↓
6. Neurotransmitter binds to receptors on the postsynaptic neuron
↓
7. Ligand-gated ion channels open
↓
8. Ions flow → postsynaptic potential occurs

Resting Membrane Potential

-membranes electrical difference at rest = -70mV

-inside neuron more negative than outside, K tends to move out of neuron

-K leak channels: since K is pos charged, since pos charge leaves inside is neg

NA/K Pump, requires ATP, moves 3 NA out and 2 K in, net movement of one positive charge out of the cell

Membrane Proteins Responsible for Electrical Function

1. Passive ion channels, always open, allow certain ions to flow

2. NA/K pump, uses atp and moves na/k

3. voltage dependent Na/K channels, open in response to changes in membrane voltage

4. Neurotransmitter receptors/ligand, open when NT binds

EPSP vs IPSP

EPSP= excitatory postsynaptic potential

—temporary depolarization of postsyn. neuron

-makes neuron more likely to fire an AP, less negative (-40mv)

IPSP= inhibitory postsynaptic potential

—temporary hyperpolarization

-makes neuron less likely to fire an AP, more negative(-100mv)

Integration: neuron receives many EPSPs and IPSPs at same time

EPSP + EPSP + EPSP = action potential

EPSP + IPSP = no action potential, cancellation,

Action Potential Generation via voltage gated NA and K channels

The sequence you REALLY need to know:

Resting potential
↓
Threshold is reached
↓

Na⁺ channels open

↓
Na⁺ flows INTO neuron
↓

Depolarization

↓
K⁺ channels open
↓
K⁺ flows OUT
↓

Repolarization

↓
Channels close
↓

Refractory period

↓
Returns toward resting potential

Voltage gated Na and K Channels cont, how they work

Voltage-gated Na⁺ channels

When the membrane reaches threshold:

—Na⁺ channels open → Na⁺ enters

Because positive charge enters: membrane becomes less negative → depolarization

—Na⁺ channels open first.

---

Voltage-gated K⁺ channels

After the Na⁺ channels have opened:

—K⁺ channels open → K⁺ leaves

Positive charge leaving the neuron causes: membrane becomes more negative again → repolarization

rate code is what

neuron tuning properties: Neurons produce action potentials (Spikes) in response to certain stimuli

but not others.

Neurons are ‘tuned’ to certain features or stimuli because they produce different rates (spikes/second)

of spikes for different features. This is known as the rate code: Individual neurons encode information about

sensory stimuli by varying their firing rate (number of spikes)

neuronal ensemble and engram

Neuronal ensemble

A group of neurons that work together to represent or process a particular piece of information.

For example:

• A group of neurons may become active together when you see a particular object.

Engram

An engram is the physical/neural representation of a memory.

Think:

Neuronal ensemble = group of neurons involved

Engram = physical neural trace associated with a memory, imprint left in brain by memory

Synaptic Potentiation vs Synaptic Depression

Potentiation:

is a strengthening of a synaptic connection. It occurs when there is a strong and

repeated activation of synapses. The stronger the activation, the longer the

potentiation: short-term (STP) or long-term (LTP).

• Depression:

is a weakening of a synaptic connection. It occurs when there is a weak or infrequent

activation of synapses over time. short-term (STD) or long-term (LTD)

4 phases of synaptic potentiation based on duration and molecules: STP, LTP1, LTP2, LTP3

STP (10-60mins)/ early stage LTP/ LTP1 (1-3 hrs) =require the activity of enzymes. No new proteins nor synaptic growth

Late stage LTP2: several days

Late stage LTP3: several weeks

LTP3 and LTP2 require activity of the enzymes and synthesis of new proteins and synaptic growth

What is a generic signaling cascade

chain of chemical reactions inside a cell that begins wehn external signal activates a receptor

The basic sequence is:

First messenger → receptor → intracellular signaling → changes in synapse

first messenger= external signaling molecule EX. Glutamate

second messenger is a molecule inside cell that helps trasnmit the signal Ex. calcium/ Ca, triggers biochemical reactions involved in plasticity

whats the best known signaling cascade leading to neuroplasticity

the best-known cascade leading to neuroplasticity occurs at glutamatergic

synapses and involves AMPA and NMDA receptors. When glutamate binds to

NMDA receptors, calcium (Ca²⁺) ions enter the cell.

—Calcium's relatively small

concentration doesn't heavily

influence the resting potential.

However, it is crucial in signaling

cascades underlying plasticity.

Calcium acts as a second

messenger, triggering biochemical

reactions inside the cell

short term vs long term plascticity

Short-term changes:

• Depend on the activity of existing enzymes

• Do not require new protein synthesis

• Do not require new synaptic growth

Long-term plasticity

Long-term changes:

• Require enzyme activity

• Require new protein synthesis

• Can involve synaptic growth

Glutamatergic synapses + 2 major glut. receptors

Glutamate = primary excitatory neurotransmitter

important for: info transmission, learning, memory, neuroplasticity

2 MAJOR REC.= AMPA and NMDA

AMPA VS NMDA

AMPA= main ion is Na, when AMPA rec. opens Na enters and the postsynaptic neuron becomes depolarized, not same Mg block, responds to glutamate

NMDA= Na & Ca enter, K can flow out, NMDA rec. allows Ca into the cell triggering signaling cascades involved in plasticity, has Mg block, requires glutamate and depolarization

NMDA activation cont.

both a ligand dependent and voltage dependent receptor

2 REQUIREMENTS

1. glutamate binds to NMDA

2. membrane must already be depolarized

—depolarization removes the <g block from the rec. then Ca can enter then signaling cascade beings= leads to neuroplasticity

The sequence to memorize:

Glutamate → AMPA opens → Na⁺ enters → depolarization → Mg²⁺ block removed → NMDA opens → Ca²⁺ enters → plasticity

—NMDA receptors are regulated and have multi binding sites,

influenced by norepinephrine, acetylcholine, dopamine, serotonin, can reduce or enhance NMDA rec. function

The Calcium and CaMKII pathway

Glutamate

↓

NMDA receptor

↓

Ca²⁺ enters

↓

CaMKII activated

↓

Postsynaptic changes

CaMKII = Ca²⁺/calmodulin-dependent protein kinase II

It contributes to postsynaptic potentiation by:

• Increasing AMPA receptor conductance

• Increasing the number of AMPA receptors inserted into the membrane

So:

More AMPA receptors → stronger postsynaptic response

Activation of kinases in CAMKII=

POSTSYNAPTIC CHANGES:

o Increased conductance in

AMPA receptors

o Insertion of additional AMPA

receptors . Activate retrograde

messengers (nitric oxide,

arachidonic acid) leads to

PRESYNAPTIC CHANGES:

increase in

neurotransmitter release

Kinases (enzymes) vs Phosphatases

Kinases = Phosphorylate other proteins. Often involved in

synaptic potentiation

Phosphorylation is the addition of a phosphate (PO43−) group to an

organic compound.

Phosphatases = Dephosphorylate proteins. Often involved in

synaptic depressio

What are silent synapses

ss= excitatory glutamatergic synapse that has NMDA rec and NO AMPA rec.

-without AMPA rec. synapse cannot produce normal depolarization needed to remove Mg block from NMDA rec.= functionally silent

How does a silent synapse become active?

Neural activity causes:

Depolarization → Mg²⁺ block removed → NMDA activation → AMPA receptors recruited → synapse becomes active

implications for disease (fragile x syndrome)

Fragile X syndrome:

• Is a genetic disorder, usually autism, mutation in single gene in X chromosome

• Is associated with intellectual disability

• Is often associated with autism

• Involves a mutation affecting the FMR1 gene

in mouse models silent synapses persist longer than normal, spine density is higher, synapse elimination is dysfunctional, and there can be more synapses but they fail to become functional

retrograde messengers that induce presynaptic changes in neuroplasticity

Postsynaptic activity can trigger the release of retrograde messengers (e.g., nitric oxide, arachidonic acid) that travel back across the synapse.

retrograde messengers: nitric oxide and arachidonic acid

signaling goes : Postsynaptic → retrograde messenger → presynaptic, can lead to increased NT release

Molecules involved in long-term cascades

LT plasticity requires: enzymes/kinases/new protein synthesis/synaptic growth

Kinases

Kinases are enzymes that add phosphate groups to proteins (phosphorylation).

Important kinases include:

• CaMKII — activated by Ca²⁺ and involved in strengthening synapses.

• MAP kinase — part of the signaling cascade that leads to changes in gene expression.

CREB

CREB = cAMP Response Element-Binding protein

• CREB is a transcription factor, bind to cAMP response elements and increases or decreases transcription of genes

• highly conserved in evolution, diverse function

• It helps turn genes on or off.

• When activated, CREB helps activate genes that support long-term memory, can be affected by antidepressants, drugs, sleep

basic pathway for long term mem through late long term plasticity

The basic pathway is:

Ca²⁺ → CaMKII/MAP kinase → CREB → immediate early genes → late-response genes → new proteins → synaptic changes

what are immediate and late response genes

Immediate early genes (IEGs):

• Activated rapidly after strong neuronal activity., only 40 identified

• Their proteins act as transcription factors, influence synaptic plasticity by regulating expression of other genes

Late-response genes:

• Activated after the immediate early genes.

• Produce proteins needed for long-term synaptic changes.

• Examples include genes involved in producing AMPA receptors and actin/cytoskeleton proteins.

what are cytoskeleton actin proteins/what do they do

The cytoskeleton is a network of protein filaments (actin) that helps determine the structure of a neuron and its synapses.

Actin is an important cytoskeleton protein.

During long-term potentiation:

• New actin can be produced.

• Actin is incorporated into the postsynaptic area.

• This can enlarge/change the structure of the postsynaptic terminal.

• Changes in actin can alter dendritic spine shape and structure.

So, actin helps physically change the synapse to support long-term plasticity.

-opposite occurs in LTD

What is synaptic tagging and capture hypothesis

When a synapse receives strong stimulation:

1. Signaling cascades that produce new mRNAs for new proteins are activated.

2. The stimulated synapse creates a temporary synaptic tag.

3. Newly produced proteins travel from the cell body.

4. The tagged synapse captures these proteins.

5. This helps produce long-lasting synaptic changes.

-tag is temporary and will disappear if no mRNAs/placticity related proteins presnts itself for the capture

flashbulb mems correlated to neural activity

Flashbulb memories are vivid and detailed memories of significant events, often associated with strong emotional responses.

They can feel especially clear and long-lasting because emotionally charged situations can produce strong neural activity and engage mechanisms involved in synaptic plasticity.

Key idea:
Strong emotional/significant events → strong neural activity → mechanisms that support long-term memory.

role of epigenetics in memory formation

Epigenetics refers to heritable changes in gene expression that occur without altering the

underlying DNA sequence.

• Unlike genetic mutations, epigenetic modifications are reversible, but they modify how cells read

the DNA, impacting gene expression and the processes that depend on it such as learning and

memory.

Epigenetic factors:

• Diet

• Exercise

• Stress

• Disease

• Exposure to chemical toxins

or drugs