Lecture 2 Exam 3 340

Sometimes an input can have the OPPOSITE effect as LTP → sometimes it can

WEAKEN

Sometimes an input can have the OPPOSITE effect as LTP → sometimes it can WEAKEN =

= Long-Term Depression (LTD)

—?— frequency stimulation produces LTD

LOW

—?—- frequency stimulation produces LTP

HIGH

Psychological factors influence observation of LTP or LTD:

• NOVEL environment w/ a STRESSED animal → observe ?

(observe) LTD

Both LTP and LTD depend on——

the NMDA Receptor

If you ONLY had LTP:

you would be able to learn but eventually your network gets SATURATED (all the inputs connect together making it harder and harder for networks to discriminate & your brain would get full)

If you ONLY had LTP: you would be able to learn but eventually your network gets SATURATED (——?——-)

(all the inputs connect together making it harder and harder for networks to discriminate & your brain would get full)

The LTD KEEPS the network from—-

getting TOO SATURATED 

The LTD KEEPS the network from getting TOO SATURATED 

• The depression helps keep you in an ——?—— where the network is actually functional where each input produces a DISTINCT activity pattern in the output network

INTERMEDIATE ZONE

The LTD KEEPS the network from getting TOO SATURATED 

• The depression helps keep you in an INTERMEDIATE ZONE where the network is actually functional where each input produces ——— in the output network

a DISTINCT activity pattern in the output network

You need BOTH LTD & LTP:

• LTP ——-connections

• LTD keeps connections from getting saturated

ENABLES

You need BOTH LTD & LTP:

• LTP ENABLES connections

• LTD keeps ——-?—- from getting saturated

(keeps) connections

What kind of network is this?

An Untrained Network

What kind of network is this?

A Trained Network

What kind of network is this?

A Saturated Network

LTP length depends on structural modifications:

growing new synaptic connections (which depends on Gene expression & Protein synthesis)

LTP length depends on structural modifications:

• growing new synaptic connections (which depends on ——?——-)

(Gene expression & Protein synthesis)

LTP length depends on structural modifications:

• growing new synaptic connections (which depends on Gene expression & Protein synthesis)

  • Uses CREB to engage ——-?——

genes that enable Long-term synaptic modification that enable things like anoretic sprouting and more connections to be formed

LTP length depends on structural modifications:

• growing new synaptic connections (which depends on Gene expression & Protein synthesis)

• Uses CREB to engage genes that enable Long-term synaptic modification that enable things like anoretic sprouting and more connections to be formed

  • CREB gets engaged →

Gene transcription factors get engaged

LTP length depends on structural modifications:

• growing new synaptic connections (which depends on Gene expression & Protein synthesis)

• Uses CREB to engage genes that enable Long-term synaptic modification that enable things like anoretic sprouting and more connections to be formed

• CREB gets engaged → Gene transcription factors get engaged →

→ which makes proteins 

LTP length depends on structural modifications:

• growing new synaptic connections (which depends on Gene expression & Protein synthesis)

• Uses CREB to engage genes that enable Long-term synaptic modification that enable things like anoretic sprouting and more connections to be formed

• CREB gets engaged → Gene transcription factors get engaged → which makes proteins →

→ that then enables long term modifications

How to test if a new kind of learning/ memory is dependent on the NMDA receptor: 

Use drug NMDA receptor ANTAGONISTS ( like APV or MK-801)

Drug NMDA receptor ANTAGONISTS:

APV & MK-801

How to test if a new kind of learning/ memory is dependent on the NMDA receptor: 

• Use drug NMDA receptor ANTAGONISTS ( like APV or MK-801)

  • APV and MK-801 ——-?——

BLOCK activity at the NMDA receptor = NMDA receptor antagonists

How to test if a new kind of learning/ memory is dependent on the NMDA receptor: 

• Use drug NMDA receptor ANTAGONISTS ( like APV or MK-801)

  • APV and MK-801 BLOCK activity at the NMDA receptor = NMDA receptor antagonists

Suppose:

• Before the strong depolarization → give NMDA antagonist drug (APV or MK-801) =

= NO LTP

How to test if a new kind of learning/ memory is dependent on the NMDA receptor: 

• Use drug NMDA receptor ANTAGONISTS ( like APV or MK-801)

  • APV and MK-801 BLOCK activity at the NMDA receptor = NMDA receptor antagonists

Suppose:

• Before the strong depolarization → give NMDA antagonist drug (APV or MK-801) = NO LTP

• Induce LTP → give NMDA receptor antagonist drug (APV or MK-801) =

NO EFFECT ON LTP

NMDA receptor antagonist drugs block the ——?——- of LTP but not the —-?—— of LTP

INDUCTION , ( not the) MAITENECE/ EXPRESSION

Morris Water Maze:

• Give MK-801 BEFORE placing rat in water maze → next day put rat in the water maze →

the rat will NOT REMEMBER where the hidden platform is

Morris Water Maze:

• Allow rat to learn water maze → then give MK-801 →

the rat WILL be able to remember where the hidden platform is (LTP maintenance is NOT affected)

Morris Cued Water Maze:

Morris CUED water maze (doesn’t require hippocampus0 → NMDA receptor antagonist ——?——-

has NO effect

Systemic Injection:

take needle w/ drug and put it in rat’s belly → the drug goes EVERYWHERE or placing drug directly into the hippocampus

Systemic Injection: take needle w/ drug and put it in rat’s belly → the drug goes EVERYWHERE or placing drug directly into the hippocampus→

→ has the same effect 

Context-conditioning (requires hippocampus):

• Give APV before context + shock → give rat context + shock→ test the next day→

the next day the rat will show NO FEAR to the context (context-dependent memory did NOT form)

Context-conditioning (requires hippocampus):

• Give context + shock → then give APV → test the next day →

• the rat WILL SHOW FEAR (freezing)

Gene targeting: knockout & transgenic

Evidence:

• Impact of knocking out CaMKII (alpha subunit):

Disrupts hippocampal LTP and spatial learning

Gene targeting: knockout & transgenic

Evidence:

• A conditional knockout for CaMKII:

• Mutation was only expressed when deoxycycline was removed from the diet

  • When mutation was expressed, LTP & spatial learning were disrupted

Gene targeting: knockout & transgenic

Evidence:

• Making a smarter mouse “Doogie” :

• Created mice that made the NR2B subunit of the NMDA receptor into adulthood

  • Exhibited enhanced LTP and learning 

Evidence that particular genes are playing a role (peg an effect to a particular protein & gene expression that produces a particular protein inside the cell):

• Knockout Genes

• Transgenics

Evidence that particular genes are playing a role (peg an effect to a particular protein & gene expression that produces a particular protein inside the cell):

• Knockout Genes:

• (Removing gene)

• take a bad gene and insert it into the mouse genome -> that mouse and its offspring would have a bad gene 

  • Answers if a particular gene plays an essential role then knocking it out should eliminate the capacity to perform that role

Evidence that particular genes are playing a role (peg an effect to a particular protein & gene expression that produces a particular protein inside the cell):

• Knockout Genes:

  • (Removing gene)

  • take a bad gene and insert it into the mouse genome → that mouse and its offspring would have a bad gene 

    • Answers if a particular gene plays an essential role then ——

knocking it out should eliminate the capacity to perform that role

Evidence that particular genes are playing a role (peg an effect to a particular protein & gene expression that produces a particular protein inside the cell):

• Transgenics:

• (Inserting gene)

  • Put in a gene that produces a new protein product that enables a new function

Evidence that particular genes are playing a role (peg an effect to a particular protein & gene expression that produces a particular protein inside the cell):

• Transgenics:

  • (Inserting gene)

    • Put in a gene that ——

produces a new protein product that enables a new function

• Knockout Genes: =

• = (Removing gene)

• Transgenics=

• = (Inserting gene)

CAMK11 is essential in

NMDA-mediated plasticity

CAMK11 is actually composed of

various subunits

CAMK11 alpha subunit:

• distribution is relatively selective

• Used to form the CAMK11 in the hippocampus

Targeting CAMK11:

• Because CAMK11 is throughout the body and plays a role in many physiological functions, if you simply knockout the CAMK11 →

• -> you wind up with a dead mouse

Targeting alpha subunit of CAMK11:

• Knocked out alpha subunit in a line of mice → that disrupted the development of LTP in their hippocampus

Targeting alpha subunit of CAMK11:

• Knockout alpha subunit→ put mice in water maze →

→ mice DO NOT learn in maze

Targeting alpha subunit of CAMK11:

• Knockout alpha subunit→ context conditioning →

• mice DO NOT learn context

Targeting alpha subunit of CAMK11:

• Knocked out alpha subunit in a line of mice → that disrupted the development of LTP in their hippocampus

  • Mice do poor in hippocampal-dependent tasks, suggesting that this particular protein (CAMK11) ——

plays a critical role in learning & memory

Targeting alpha subunit of CAMK11:

• Knocked out alpha subunit in a line of mice → that disrupted the development of LTP in their hippocampus

  • Mice do poor in hippocampal-dependent tasks, suggesting that this particular protein (CAMK11) plays a critical role in learning & memory

• Knockout alpha subunit →

→Reduce LTP

Another problem is if you knockout a particular gene, other processes may

come to bear to compensate

• Another problem is if you knockout a particular gene, other processes may come to bear to compensate -> need a more selective process =

• conditional knockout

Conditional Knockout:

• Take a part of the bacterial system (a bacterial promoter called the TET-O promoter) → tie engagement of TET-O promoter to the manufacturing of a mutant form of this CAMK11

  • Whether mutant CAMK11 is expressed is dependent on TET-O

  • For TET-O to be turned on it requires TTA

    • Once TTA is there to turn on TET-O,  mutant CAMK11will be expressed and now mouse would be “dumb”

• Because mice don’t normally make TTA you need another line of mice that have been modified to make TTA

  • Couple the production of TTA to the alpha subunit of CAMK11→ so mouse makes TTA in the alpha subunit of CAMK11 in the hippocampus where it is normally expressed

• Pair mouse that makes TTA with the mutant CAMK11 controlled by TET-O promoter to reproduce → to produce a mouse that makes TTA in the hippocampus that will turn on the TET-O and make mutated CAMK11

Conditional Knockout:

• Take a part of the bacterial system (a bacterial promoter called the TET-O promoter) → tie —-?——- to ——-?——

engagement of TET-O promoter , (to) the manufacturing of a mutant form of this CAMK11

Conditional Knockout:

• Take a part of the bacterial system (a bacterial promoter called the TET-O promoter) → tie engagement of TET-O promoter to the manufacturing of a mutant form of this CAMK11

  • Whether mutant CAMK11 is expressed is dependent on ——?—

TET-O

Conditional Knockout:

• Take a part of the bacterial system (a bacterial promoter called the TET-O promoter) → tie engagement of TET-O promoter to the manufacturing of a mutant form of this CAMK11

  • Whether mutant CAMK11 is expressed is dependent on TET-O

    • For TET-O to be turned on it requires—-?—-

TTA

Conditional Knockout:

• Take a part of the bacterial system (a bacterial promoter called the TET-O promoter) → tie engagement of TET-O promoter to the manufacturing of a mutant form of this CAMK11

  • Whether mutant CAMK11 is expressed is dependent on TET-O

  • For TET-O to be turned on it requires TTA

    • Once TTA is there to turn on TET-O,  —-?—- will be expressed and now mouse would be “dumb”

mutant CAMK11

Conditional Knockout:

• Take a part of the bacterial system (a bacterial promoter called the TET-O promoter) → tie engagement of TET-O promoter to the manufacturing of a mutant form of this CAMK11

  • Whether mutant CAMK11 is expressed is dependent on TET-O

  • For TET-O to be turned on it requires TTA

    • Once TTA is there to turn on TET-O,  mutant CAMK11will be expressed and now mouse would be “dumb”

• Because mice don’t normally make TTA you need ——-

another line of mice that have been modified to make TTA

Conditional Knockout:

• Take a part of the bacterial system (a bacterial promoter called the TET-O promoter) → tie engagement of TET-O promoter to the manufacturing of a mutant form of this CAMK11

  • Whether mutant CAMK11 is expressed is dependent on TET-O

  • For TET-O to be turned on it requires TTA

    • Once TTA is there to turn on TET-O,  mutant CAMK11will be expressed and now mouse would be “dumb”

• Because mice don’t normally make TTA you need another line of mice that have been modified to make TTA

  • Couple the production of TTA to——?——

the alpha subunit of CAMK11

Conditional Knockout:

• Take a part of the bacterial system (a bacterial promoter called the TET-O promoter) → tie engagement of TET-O promoter to the manufacturing of a mutant form of this CAMK11

  • Whether mutant CAMK11 is expressed is dependent on TET-O

  • For TET-O to be turned on it requires TTA

    • Once TTA is there to turn on TET-O,  mutant CAMK11will be expressed and now mouse would be “dumb”

• Because mice don’t normally make TTA you need another line of mice that have been modified to make TTA

  • Couple the production of TTA to the alpha subunit of CAMK11→

→ so mouse makes TTA in the alpha subunit of CAMK11 in the hippocampus where it is normally expressed

Conditional Knockout:

• Take a part of the bacterial system (a bacterial promoter called the TET-O promoter) → tie engagement of TET-O promoter to the manufacturing of a mutant form of this CAMK11

  • Whether mutant CAMK11 is expressed is dependent on TET-O

  • For TET-O to be turned on it requires TTA

    • Once TTA is there to turn on TET-O,  mutant CAMK11will be expressed and now mouse would be “dumb”

• Because mice don’t normally make TTA you need another line of mice that have been modified to make TTA

  • Couple the production of TTA to the alpha subunit of CAMK11→ so mouse makes TTA in the alpha subunit of CAMK11 in the hippocampus where it is normally expressed

• Pair —-?—- with ——?—- to reproduce

the mouse that makes TTA (with) the mutant CAMK11 controlled by TET-O promoter

Conditional Knockout:

• Take a part of the bacterial system (a bacterial promoter called the TET-O promoter) → tie engagement of TET-O promoter to the manufacturing of a mutant form of this CAMK11

  • Whether mutant CAMK11 is expressed is dependent on TET-O

  • For TET-O to be turned on it requires TTA

    • Once TTA is there to turn on TET-O,  mutant CAMK11will be expressed and now mouse would be “dumb”

• Because mice don’t normally make TTA you need another line of mice that have been modified to make TTA

  • Couple the production of TTA to the alpha subunit of CAMK11→ so mouse makes TTA in the alpha subunit of CAMK11 in the hippocampus where it is normally expressed

• Pair mouse that makes TTA with the mutant CAMK11 controlled by TET-O promoter to reproduce → to produce —-?—-

a mouse that makes TTA in the hippocampus that will turn on the TET-O and make mutated CAMK11

Conditional Knockout:

Giving the animal Doxycycline can —-

turn this system on & off

Conditional Knockout:

Giving the animal Doxycycline can turn this system on & off

• If DOX is in the food→

it binds to TTA so it can’t bind to TET-O

Conditional Knockout:

Giving the animal Doxycycline can turn this system on & off

• If DOX is in the food→ it binds to TTA so it can’t bind to TET-O →

→preventing the expression of the mutant CAMK11

Conditional Knockout:

Giving the animal Doxycycline can turn this system on & off

• Raise rat w/ DOX in their diet →

mutant CAMK11 never expressed and mouse is normal

Conditional Knockout:

Giving the animal Doxycycline can turn this system on & off

• Raise rat w/ DOX in their diet → mutant CAMK11 never expressed and mouse is normal → then take DOX out of diet →

now mutant CAMK11 is expressed

Conditional Knockout:

Giving the animal Doxycycline can turn this system on & off

• Raise rat w/ DOX in their diet → mutant CAMK11 never expressed and mouse is normal → then take DOX out of diet → now mutant CAMK11 is expressed → after a few days →

hippocampus LTP goes away

Conditional Knockout:

Giving the animal Doxycycline can turn this system on & off

• Raise rat w/ DOX in their diet → mutant CAMK11 never expressed and mouse is normal → then take DOX out of diet → now mutant CAMK11 is expressed → after a few days → hippocampus LTP goes away

  • The ability to learn in———?——- goes away

    • Give mouse DOX again and hippocampus LTP comes back

(in) hippocampus -dependent tasks