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Animal models > Lecture Grandjean > Flashcards

Lecture Grandjean Flashcards

1
Q

Learning goals

A
  • the student can put the monoamine hypothesis for depression into a historical context
  • the student can discuss imaging-based approaches to study depression and associated symptoms
  • the student can discuss the relevance of animal models for stress disorders
  • the student can propose strategies to study stress in animal models
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2
Q

where do antidepressants come from

A

tuberculosis drug which was found to have positive mood enhancing side effects.

this is because its molecular compositionn looks very similar like dopamine noradrenaline and serotonine

enzime monoamine oxidase, switches NH2 (amine) with OH (carboxilic group)

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3
Q

What i the recurrent target for antidepressants?

A

The monoamine oxidase (MOA) is the recurrent target for antidepressants

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4
Q

What did the rise of serotonine hypothesis in the1990s lead to

A

selective serotonin reuptake inhibitors ssris, e.g. prozac

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5
Q

What did geneticists find out in the 1990s?

A

that there was a common polymorphism in its upstream from the serotonin transporter gene, and people with this polymorphism have a greater susceptibility for depression and anxiety

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6
Q

fall of serotonine hypothesis 2020s

A
  • collaborative meta-analysis finds no evidence of a strong interaction between stress and 5-HTTLPR genotype contributing to the development of depression
  • systematic review - the serotonin theory of depression: a systematic umbrella review of the evidence

BUT

not completely dead, but only 15% of the case relative to placebo

Analysis of >230 clinical trial with >70K participants

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7
Q

What is depression?

A

Inducing factors:

  • chronic stress
  • trauma
  • substance abuse
  • inflammation

vulnerabilitie:

  • genetic predesposition
  • environmental predisposition

Comorbidities:

  • Anxiety disorders
  • dementia
  • type 2 diabetes
  • coronary artery disease
  • parkinson’s disease
  • epilepsy
  • pain
  • cancers
  • aging
  • osteoporosis
  • irritable bowel syndrome
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8
Q

What are the symptoms of depression?

A
  • reduced mood
  • anhedonia
  • anergia
  • irritability
  • diffiulty concentrating
  • disrupted sleep
  • disrupted appetite
  • disrupted cognition
  • suicidal thoughts
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9
Q

how is sickness behavior related to depression

A

if you are sick you will not propagate sickness if you keep to yourself - inflammation.

sickness behaviour as evolutionary explanation for depression

sickness symptoms overlap with those of depression. Could they have the same underpinnings?

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10
Q

Imaging methods for human brain

A

Magnetic resonance for the human brain

  • structural imaging (anatomy)
  • diffusion imaging (white matter)
  • functional imaging (rest)
  • functional imaging (task)

Nuclear imaging (SPECT/PET)

  • metabolism
  • dopamine transporter
  • dopamine receptor D2
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11
Q

Depression is associated with reduced blood flow in the subgenual cingulate

A

first PET (radioactive water was injected), water goes where blood goes

depression vs healthy participants

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12
Q

Lesion study for association with depression

A

Lesions in insula and dorsolateral prefrontal cortex are associated with depression

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13
Q

Neuroquery

A

Quick meta-analysis for ‘depression’ - literature erichment clusters in the cingulate and insula areas

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14
Q

the human brain is organized into distributed networks that co-activates at rest and during tasks

A
  • Visual network
  • Auditory network
  • Posterior default-mode network
  • Central executive network
  • anterior default-mode network
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15
Q

What is the triple-network model of psychopathology

A

on average across disorders, it tends to always be 3 big main networks: Salience (SN), Central Executive (CEN) and Default-Mode Networks (DMN)

usually you either have CE (external stimuli) or you have inner thoughts - DMN (default-mode networks) and then the Salience network integrates integration, decides if information is relevant and decides whether CE or DMN is activated

Depression - rumination - correlated with DMN

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16
Q

Serotonin and dopamine are thought to exert opposite effects on brain networks

A

manic state
depressive state
psychotic s

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17
Q

Some neural ensembles of the human brain are derived from old structures

A

zebrafish - 3-8 neurons are thought to release serotonin

chicken/xenopus - ca 8 neurons are thought to release dopamine

C. elegans (worm) - has 302 neurons out of 1000 somatic cells

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18
Q

How do you replicate depressive symptoms in animal models?

A
  • social stress
  • chronic mild stress
  • maternal separation
  • genetic models

A variety of models can be used to study depressive symptoms in animals. There are either due to
- behavioural induction (social stress, chronic stress, maternal separation),

  • genetic models such as selective breeds (Winstar-Kyoto) and transgenics (SERT-KO), or
  • interventions (lipopolysaccharide)
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19
Q

How to assess depressive symptoms in animal models

A
  • water maze
  • forced swim test
  • open field
  • elevated + maze
  • sucrose preference test
  • rotarod

A variety of test are commonly used to assess
- memory (water maze),
- negative mood (force swim test), - anxiety (open field, elevated + maze),
- anhedonia (sucrose preference test),
- fatigue (rotarod).

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20
Q

Modulation depression targets with deep brain stimulation

A

Works very well for parkinsons disease

Atlas Target

Pre-op MRI Target Localization

Post-op MRI Electrode Location

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21
Q

Testing the role of the prefrontal cortex in behaviours associated with depression

A

coil trace with individual kicks (when animals are trying to fihgt off Changes in voltage of coil

22
Q

Neurons are hypoactive during forced swim test, except during mobile phase

A

when they are kicking (fight for life) swimming –>

Neuronal activity with electroden into mPFC

Forced swim test (mobile) higher firing rate

forced swim test (immobile) lower firing rate

part where they are kicking (fighting for their life) associated with higher neuronal activity pfc

23
Q

Elevating PFC neurons activity with optogenetics does not change kicking frequency

A

overactivating PFC neurons does not lead the rat kick

24
Q

Elevating activity in PFC - dorsal raphe projection (DRN - dorsal raphe nucleus), induces kicking

A

BUT only DRN stimulation does not give as much of a response

25
Q

Circuit between PFC and serotonin neurons not only serotonine

A
26
Q

How to perform imaging studies in animals dedicated systems

A

Problematic:

  • mouse brain is 1000x smaller
  • MRI resolution in human is 1x1x1mm^3
  • MRI resolution in mice is 0.1 x0.1 0.1 mm^3
  • Low signal-to-noise ration

Animals are not complient (anethtesized or fixation)

27
Q

Animal functional imaging replicates several brain networks found in humans

A
28
Q

Optogenetics can be applied concurrently with functional imaging.

A
29
Q

Prefrontal cortical regulation of brainwide circuit dynamics and reward-related behavior - optogenetics can be applied concurrently with functional imaging

A
30
Q

The VTA dopamine circuit

A

does send dopamine projections from Midbrain to nucleus accumbens (mesolimbic DA pathway) or to the ventromedial prefrontal cortex (Mesocortical DA pathway)

31
Q

Setting up awake rat MRI

A

Animal surgery took 7h per rat (!!)
Why use visual stimulation?

  • control for when the optogenetic light is on
32
Q

Targeing DA neurons in the rat brain

A

Using transgenic rats

33
Q

What is Cre/Low system

A

Cre (Cyclization Recombination Enzyme): This is a special enzyme that can cut DNA at specific sites. It recognizes a short DNA sequence called LoxP.

LoxP: This is a specific sequence of DNA that is placed around the gene or DNA region of interest.

The Process:

In a Cre-Lox system, scientists insert the LoxP sequences on either side of a gene or DNA region they want to control.
The Cre enzyme then cuts the DNA between the LoxP sites, which can either remove the gene, invert it, or cause other changes depending on how it’s engineered.
The result is that the gene is “turned off” or modified in a specific tissue, at a certain time, or in response to a certain trigger.

34
Q

most commonly used genes for optogenetics

A

channelrhodopsins

halorhodopsins

35
Q

hjjacke dopamine neurons and control them with light

A

Functional imaging during DA neuron stimulation

36
Q

Why keep using visual stimulation?

A

Have a control

37
Q

Is the optogenetics - fMRI response what you would expect?

A
38
Q

Why YFP control?

A
39
Q

If you stimulate VTA what would you expect brain activity?

A

Where it projects to, i.e. ….

40
Q

Behavioural outcomes to DA stimulation

A

animal taken outside of scanner, rat is faced with 2 levers and if they do light is done on VTA.
Active lever –>

ChR2 lever presses go up
YFP controls lever presses do not go up

Inactive lever

ChR2 lever presses do not go up

YFP lever presses do not go up

Is this what you would expect? Why?
Does this remind you of any classical kind of experiments?

41
Q

Optogenetics + 2 drugs

A

when you block the receptors you can block the response

if you block dopamine, visual response goes up

42
Q

other methods to do long neuromodulation alternative to stabilised-step function

A

chemogenetics, taking receptor that binds to one of your neurotransmitter. You make it evolve all the way until it does not bind and then it binds to a molecule that does not do anything else. receptor that binds to molecule that does not bind to anything else

43
Q

chemogenetics

A
44
Q

Targeting prefrontal cortex

A

optogenetics vs chemogenetics

45
Q

Photoactivation of the prefrontal cortex

A

they do test to see if animals have hedonia or anhedonia

offer sweet stuff or water

When prefrontal cortex is hyperactivated they consume less of the sweet stuff on average

Social interaction: baby mouse - social endurences decrease when hyperactivated prefrontal cortex

46
Q

Is the change in behaviour evoked with SSFO activation of the PFC pro- or anti-depressive?

A

pro

47
Q

Combined photostimulation of the VTA dopamine neurons and profrontal cortex

A

when you activate VTA you see activation in striatum, while prefrontal cortex you do not see anymore. Prefrontal cortex regulates VTA output (not sure)

48
Q

Do these results convince you that PFC regulates VTA output?

A

????????

49
Q

Summary

A
  • How monamine theories of depression rose to fame
  • Causes for stress and depression
  • Imaging strategies for depression
  • Modern theories for depression based on imaging outcomes
  • How to study stress/depression disorders in animals
  • How to get mechanistic information in animals using dedicated tools
  • Imaging strategies to study stress/depression disorders in animals
50
Q
A

Animal models (10 decks)

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