Lecture Grandjean Flashcards
Learning goals
- 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
where do antidepressants come from
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)
What i the recurrent target for antidepressants?
The monoamine oxidase (MOA) is the recurrent target for antidepressants
What did the rise of serotonine hypothesis in the1990s lead to
selective serotonin reuptake inhibitors ssris, e.g. prozac
What did geneticists find out in the 1990s?
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
fall of serotonine hypothesis 2020s
- 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
What is depression?
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
What are the symptoms of depression?
- reduced mood
- anhedonia
- anergia
- irritability
- diffiulty concentrating
- disrupted sleep
- disrupted appetite
- disrupted cognition
- suicidal thoughts
how is sickness behavior related to depression
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?
Imaging methods for human brain
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
Depression is associated with reduced blood flow in the subgenual cingulate
first PET (radioactive water was injected), water goes where blood goes
depression vs healthy participants
Lesion study for association with depression
Lesions in insula and dorsolateral prefrontal cortex are associated with depression
Neuroquery
Quick meta-analysis for ‘depression’ - literature erichment clusters in the cingulate and insula areas
the human brain is organized into distributed networks that co-activates at rest and during tasks
- Visual network
- Auditory network
- Posterior default-mode network
- Central executive network
- anterior default-mode network
What is the triple-network model of psychopathology
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
Serotonin and dopamine are thought to exert opposite effects on brain networks
manic state
depressive state
psychotic s
Some neural ensembles of the human brain are derived from old structures
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
How do you replicate depressive symptoms in animal models?
- 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)
How to assess depressive symptoms in animal models
- 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).
Modulation depression targets with deep brain stimulation
Works very well for parkinsons disease
Atlas Target
Pre-op MRI Target Localization
Post-op MRI Electrode Location
Testing the role of the prefrontal cortex in behaviours associated with depression
coil trace with individual kicks (when animals are trying to fihgt off Changes in voltage of coil
Neurons are hypoactive during forced swim test, except during mobile phase
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
Elevating PFC neurons activity with optogenetics does not change kicking frequency
overactivating PFC neurons does not lead the rat kick
Elevating activity in PFC - dorsal raphe projection (DRN - dorsal raphe nucleus), induces kicking
BUT only DRN stimulation does not give as much of a response
Circuit between PFC and serotonin neurons not only serotonine
How to perform imaging studies in animals dedicated systems
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)
Animal functional imaging replicates several brain networks found in humans
Optogenetics can be applied concurrently with functional imaging.
Prefrontal cortical regulation of brainwide circuit dynamics and reward-related behavior - optogenetics can be applied concurrently with functional imaging
The VTA dopamine circuit
does send dopamine projections from Midbrain to nucleus accumbens (mesolimbic DA pathway) or to the ventromedial prefrontal cortex (Mesocortical DA pathway)
Setting up awake rat MRI
Animal surgery took 7h per rat (!!)
Why use visual stimulation?
- control for when the optogenetic light is on
Targeing DA neurons in the rat brain
Using transgenic rats
What is Cre/Low system
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.
most commonly used genes for optogenetics
channelrhodopsins
halorhodopsins
hjjacke dopamine neurons and control them with light
Functional imaging during DA neuron stimulation
Why keep using visual stimulation?
Have a control
Is the optogenetics - fMRI response what you would expect?
Why YFP control?
If you stimulate VTA what would you expect brain activity?
Where it projects to, i.e. ….
Behavioural outcomes to DA stimulation
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?
Optogenetics + 2 drugs
when you block the receptors you can block the response
if you block dopamine, visual response goes up
other methods to do long neuromodulation alternative to stabilised-step function
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
chemogenetics
Targeting prefrontal cortex
optogenetics vs chemogenetics
Photoactivation of the prefrontal cortex
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
Is the change in behaviour evoked with SSFO activation of the PFC pro- or anti-depressive?
pro
Combined photostimulation of the VTA dopamine neurons and profrontal cortex
when you activate VTA you see activation in striatum, while prefrontal cortex you do not see anymore. Prefrontal cortex regulates VTA output (not sure)
Do these results convince you that PFC regulates VTA output?
????????
Summary
- 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
