PSYC453 - Midterm (Articles)

Flashcards for articles

Kravitz - Research Question(s)

**Experiment 1:** Does optogenetic excitation of the direct and indirect pathways lead to reinforcement and

punishment respectively?

**Experiment 2:** Is the effect observed in experiment 1 due to indirect dopamine activation?

**Experiment 3:** Does optogenetic activation of these pathways affect other behaviours in a similar manner?

Are the effects observed in experiment 1 specific to the behavioural design used?

Kravtiz - Hypothesis

They hypothesized that activation of D1 receptor-expressing dMSNs would facilitate reinforcement while D2 receptor-expressing iMSNs would facilitate punishment.

Kravitz - Experiment 1 Methods

\-Genetic targeting of channelrhodopsin (using a virus) in D1 or D2 MSNs

\-Optogenetics to activate dMSNs and iMSNs with ChR2

\-ICSS:

Two manipulanda (lever-like devices) were inserted on either side of a conditioning box

Capacitive touch devices were used as manipulanda (better for mice than levers)

One manipulanda led to laser activation – laser-paired trigger

Other manipulanda led to no laser activation – non-laser-paired trigger

Mice were trained for three days for 30 min. The fourth day (or more) consisted of ‘retraining’ and extinction sessions

Kravitz - Experiment 2 Methods

Same design as experiment 1, yet with a dopamine antagonist given:


1. Each day of the experiment
2. Only during the extinction test

Kravitz - Experiment 3 Methods

Conditioned place preference (CPP)

Two 8 x 8 inch chambers, one with black

walls one with white walls

Laser stimulation:

2 seconds on, 8 seconds off while on one

side of box

Kravitz - Results

1 - Optogenetic self-stimulation of medium spiny neurons in the dorsomedial striatum supports positive reinforcement in D1 expressing neurons (dMSNs) and transient negative reinforcement in D2 expressing neurons (iMSNs)

2 - This effect is not dependent on dopamine release

3 - The positive and negative reinforcing effects of D1- and D2-expressing MSNs are also observed in conditioned place preference (CPP*)*

Illango - Research Question

The researchers’ main question was to investigate to what degree dopamine neurons in the substantia nigra pars compacta (SNc) contribute to affective functions.

Illango - Hypothesis

They hypothesized that like dopamine neurons located in the ventral tegmental area, SNc dopamine neurons will produce positive and negative affect if excited or inhibited, respectively.

Illango - Experiment 1 Methods

ChR2

Optogenetics

ICSS (Active lever press/photostimulation)

Operant place preference/photstimulation

Illango - Experiment 2 Methods

Smaller volumes of virus encoding ChR2 injected in SNc and VTA

Sacrifice + looked at CFos counts in the SNc __and__ VTA, both ipsilateral and contralateral, after photostimulation of SNc __or__ VTA

CFos: expressed in recently active cells

Illango - Experiment 3 Methods

NpHR

Operant place preference/photostimulation

Illango - Experiment 4 Methods

Same as 3 but this experiment aims to see if inhibition of neurons in the medial dorsal striatum (mDSTr) and central medial dorsal striatum also leads to aversive effects.

Illango - Results

The present study provides evidence that the excitation and inhi- bition of SNc DA neurons induce reward and aversion, respec- tively, and the extent of these effects is similar to those of the VTA DA neurons. The present study provides first evidence that inhibition of SNc DA neurons or nigrostriatal DA projections causes aversion like that of VTA DA neurons.

Matsumoto - Research Question

Do dopamine neurons respond to cues indicating value and are they inhibited in response to aversive cues?

Matsumoto - Hypothesis

They hypothesized that (only) dopamine neurons in the VTA/SNc would respond to motivational value.

Matsumoto - Methods

Histology: Recording/Locating dopamine neurons in relation to their responses to airpuff-predicting CS

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Behavioural paradigm: Pavlovian approach where monkeys were classically conditioned to assess whether dopamine neurons are implicated in motivational value. This procedure involved giving monkeys a reward in the appetitive block or an air puff in the aversive block (unconditioned stimulus) with either 100%, 50% or 0% probability (conditioned stimulus).

Matsumoto - Results

Appetitive = Anticipatory licking increased as probability of reward increased

Aversive Block/Punishment = Anticipatory blinking increased as the probability of airpuff increased

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**Value coding: VTA & ventromedial SNc =** transmit value-related information to ventral striatum (NAc)

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**Salience: dorsolateral SNc =** Response to motivationally salient stimuli 

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**ACS-excited** = excited by reward-predicting and airpuff-predicting stimuli. (does not encode motivational value)

**•ACS-inhibited** = excited by reward-predicting stimuli and inhibited by airpuff-predicting stimuli (encodes motivational value)

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**AUS-inhibited** neurons were consistent with Reward Prediction Error whereas **AUS-excited** neurons were inconsistent with RPE because the measurements weren't in opposite directions as would have been predicted

Namburi - Research Question

How is it possible that potentiation of synapses onto neurons in the BLA underlie learned associations that lead to such different behavioural responses?

Namburi - Hypothesis

BLA projections to the NAc have been __implicated in reward-related behaviours,__ while BLA projections to the CeM have been __linked to the expression of conditioned fear.__

Namburi - Experiment 1 Methods + Results

Purpose = Examine the synaptic changes in NAc & CeM projectors after fear or reward conditioning.

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Methods:

* Retrograde tracing


* Pavlovian conditioning
* Ex vivo electrophysiology (tissue preparation + whole cell patch clamp recording)

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Results:

➔__Fear conditioning__ = AMPAR/NMDAR ratio __decreased__ **(NAc)**

➔__Reward conditioning__ = AMPAR/NMDAR ratio __increased__ **(NAc)**

➔__Fear conditioning__ = AMPAR/NMDAR ratio __increased__ **(CeM)**

➔__Reward conditioning__ = AMPAR/NMDAR ratio __decreased__ **(CeM)**

Namburi - Experiment 2 Methods + Results

Purpose = **:** Determining if there is a causal relationship between populations of projection-identified BLA neurons and behavior

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Methods:

* Used a retrogradedly infectious rabies viral vector to express ChR2 fused to a fluorescent reporter (Venus) or control virus w/ just Venus in BLA neurons projecting to NAc or CeM.
* Intracranial self-stimulation (ICSS) task

\-This task has mice engage in nose-pokes in order to receive rewarding pulses of electrical brain stimulation

\-However, ICSS only works with positive reinforcement (i.e. they can only measure NAc activity with this task)
* To test CeM projectors, the researchers used a closed-loop real-time place avoidance assay (RTPA), where a mouse freely explored two chambers, one in which the they received photostimulation (via laser) of CeM projectors
* The mouse should spend less time in the chamber where the laser is turned on

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Results:

→ most nose-pokes were in response to an active NAc ChR2 = NAc is appetitive and influences behavior

→mouse avoided CeM stimulation = aversive and also influences behavior

Namburi - Experiment 3 Methods + Results

Purpose = Test whether NAc or CeM projectors are necessary in mediating reward or fear conditioning

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Methods:

* Halorhodopsin + EYFP (fluorescent marker) to inhibit pathways during learning, genes are then double floxed (backwards) and can’t be expressed.
* Cre-recominase enzyme travels from axon to nucleus flips genes right way (cells now have halorhodopsin + EYFP and can now be inhibited when light is shined on the cell, as haloredopsin is photoinhibitive).
* Fear + reward behavioural procedures

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Results:

Photoinhibition of CeM projectors during the conditioned–unconditioned stimulus pairing impaired __conditioned freezing__ and enhanced __conditioned reward seeking__

Tindell - Research Question

The researchers’ main question was to investigate whether neuronal firing in the ventral palladium (VP) codes sensory pleasure.

Tindell - Hypothesis

The Ventral Pallidum (VP) encodes positive hedonic value

Tindell - Methods

* **Electrode implantation** for electrophysiological recording of neurons aligned to behavioural events.
* **Normal homeostasis testing:** habituated to infusions + access to NaCl solution + injected w/ solutions to provoke sodium depletion.
* **Sodium depletion testing:** 24 hours after injections, no NaCl available.
* **Sodium repletion testing:** NaCl access for 3 days, rats euthanized afterward.
* **Taste reactivity:** identify times, duration and latency of positive hedonic reactions (paw licking) and aversive reaction (face washing/gapes) + compare reaction w/ VP firing.
* **Histology:** rats euthanized, cut and stain brains, slice examined under microscope to verify electrode placement.

Tindell - Results

* Strong hedonic reaction for sucrose in homeostasis and sodium depletion conditions.
* Low Aversive reaction for sucrose in homeostasis and sodium depletion conditions.
* Hedonic reactions for NaCl: 3x stronger for depleted condition vs homeostasis (almost equal hedonic response to sucrose).
* Aversive reactions for NaCl: disliking during baseline, disliking reduced to 25% below baseline during depletion.
* Replenishment of sodium returned to aversive/disliking.
* Neural firing due to NaCl had a positive correlational relationship to behavioral hedonic scores.
* Strong evidence that aversive tastes can become pleasant if there is a change in the physiological state.