Fear & Anxiety Flashcards
Difference between fear and anxiety
Fear is related to concreate threats that leads to a reflexive response. Anxiety triggered by something more vague and ambiguous - you don’t know if it’s threatening, it’s not concrete.
Overall and life time prevalence of anxiety
overall: 15%, lifetime: 30%
females are more likely to get it
Human vs. rodent emotional expression
We express basic emotions with muscles in our faces.Rodents show subtle changes in expressions. They show some response to pain, but it’s not an emotion. We evaluate emotions in rodents based on behavior (motor patterns).
best known motor pattern for fear in rodents?
The most known motor pattern that can be quantified is freezing (for fear).
What reactions are caused by fear
emotional stimuli is received by the nervous system and the hypothalamus and the brain stem compute a response to the stimuli, which gives a response to the stimuli (affects skeletal muscles or smooth muscle/endocrine glands). It’s important to realize that these processes interact and work together to produce the fear response
Fear in humans vs animals
Humans have conscious fear with subjective feelings that can be mentally represented. Animals have unconscious emotions with non-subjective physiological states.
Bottom-up emotional model
James Lange believed that the stimulus lead to behavioral and somatic responses, which would lead to fear through interoception (we’re afraid because we run)
Top-down emotional model
Cannon-Bard proposed that there was a stimulus leading to somatic and behavioral responses. These things together led to the emotional state, which leads to subjective feelings that can be reported.
integrative model of emotions
used in animal research and is a “compromise” between the 2 previous models.
Stimuli leads to an emotional state, which leads to cognitive, behavioral and somatic responses. These reactions can influence the stimuli and thereby the emotional state
Cortical regions responsible for modulating a fear response?
PFC, amygdala and hippocampus
Regions that can modulate a fear response all deal with?
Providing context
Historical experiments showed us what about the hypothalamus?
When cutting corona-lly on a cat’s brain, we saw that agressive responses were eliminated when cutting past the mammillary bodies (post hypothalamus)
Why is the limbic system called “limbic”
because the areas form a circle around the brain stem
Issues with the limbic system
It’s important to know that this system doesn’t work alone and the area-specific effects of an area is not entirely correct. There is no one-to-one relationship between structure and function that would allow us to define an “emotion system”
Papez circuit
Added stuff to the limbic system, e.g. sensory and cingulate cortex and started the idea of an hierarchical chain of events
Observational/perturbational approaches
Observing allows us to understand correlations: it’s not invasive, but it’s a fishing expedition
Perturbations allows us to understand causation: it’s invasive, but it’s more clear what the mechanism is
ChR2 (channel rhodopsin)
reacts to blue light and is depolarizing by allowing Na+ in and K+ out (is a channel)
Arch (Archaea-rhodopsin)
A pump that allows H+ out of the cell when yellow/orange light is shone on it, leading to hyperpolerization
NpHR (Halo-rhodopsin)
A pump that allows Cl- into the cell when yellow/orange light is shone on it, leading to hyperpolerization
Cre/lox system for opsins
We use cre-mouse driver lines, where cre is coupled to genetic information about a certain cell type. There is a promotor in front of a specific gene for the cell type, and cre is therefore only expressed in that cell type. Cre itself does not lead to a phenotype.
We can now combine cre with an injection of a viral vector that delivers our opsin. We usually use adeono viruses and we inject it into our brain region of interest and infect all brain areas. The virus delivers its gene product into all cells, but it’s only expressed where cre is present. This is because the gene is “upside down”, but it has flags on each side, that cre can recognize. Cre turns the gene around, which allows the gene to be transcribed and translated.
This combination of tools allows us to express the opsin in only the cells we’re interested in
is the fear or the anxiety network more complex?
Anxiety
What is the complexity problem?
We want to understand circuits, but sometimes these are too complex, and we therefore have to analyse all the micro circuits and then connect all the information in the end.
Why do we use mice to understand fear and anxiety in humans?
While there is a large difference between humans and mice, there is a large similarity to the structure and neurological mechanisms.
2 subregions of the amygdala
central and basolateral amygdala
basolateral amygdala
Also called the cortical amydgala
- 80% glutamateric neurons, 20% GABAergic
- It received almost all inputs and project to the central amygdala. It can be subdivided into the basal and lateral nucleus of the amygdala
Central amygdala
mainly GABAergic neurons (why it’s referred to as the striatal amygdala). It’s the main output areas and it’s nuclei are the lateral and medial nucleus
Pawlovian fear conditioning
You start with the training (conditioned stimulus is CS and aversive stimulation is US)
24 hrs later you test if the mouse remember the association.
The learning paradigm is popular, as it’s robust and can be used in general learning and memory. It’s also important in anxiety learning, as there might be pathological changes
Historical/basic understanding of the amygdala anatomy
in the lateral amygdala (LA) the information comes in and is then processed to the central amygdala, which triggers a defensive response. If both signals converge in the lateral amygdala, it leads to a strong response in the LA. The CA and US meet at the synapses in the lateral amygdala and initiate LTP. The LTP leads to the 2 stimuli being associated and that CS therefore can trigger the central amygdala response alone
Can optogenetic stimulation of the projections from the auditory cortex to the lateral nucleus (those normally active for the CS) be used instead of a CS for fear condditioning?
Yes, the CS does not need to be a tone
high frequency bursts of blue light onto channel rhodopsin leads to?
LTP induction
low frequency bursts of blue light onto channel rhodopsin leads to?
LTD
Can LTD decrease the fear response in fear conditioned mice and if so, what does that mean?
Yes, it could, which means the LTP if induced in the lateral amygdala, which is how the association starts
What immediate early gene’s transcription is increased when LTP is present
cFOS
What is the theoretical concept related to LTP and cFOS?
all neurons that are involved in the formation of associate memory undergo LTP and temporally express cFOS.
What are the implication of the theoretical concept related to LTP and cFOS?
it can be used/transferred into the hypothesis that would allow us to use cFOS as a molecular marker for a certain memory trace (cFOS is expressed during the formation of the memory)
What is a memory engram?
the synchronous activity of neuronal populations across brain regions that encode a memory
Contextual fear conditioning
the mouse only receives the chock in a certain setting (environment becomes the CS). In addition to the amygdala, the hippocampus is heavily involved.
How do we tag memory engrams at the retrieval stage of fear conditioning
by utilizing the presence of cFOS in the neurons involved in retrieval
can we use optogenetics to stimulate the neurons who are involved in the memory engram and thereby have a freezing in the new environment for contextual fear learning?
Yes, if the opsins are expressed in the neurons for the memory engram
Extinction
With extinction, we present CS alone without US, which over time will lead to a decrease in the fear response
Is extinction based on LTD by tuning down the memory engram, or are we forming a new memory with the extinction?
we form a new memory that battles the old one
What does Rspo2 positive neurons in the amygdala code for?
Rspo2+ neurons encode the fear conditioning
What does Ppp1r1b positive neurons in the amygdala code for?
The extinction memory engram
the place preference test for extinction learning showed what?
That extinction could be categorized as a reward engram, as they are interchangeable in the basolateral amygdala
classical flow of information through the amygdala
we here see the parallel information stream of CS and US that converge onto the lateral nucleus of the amygdala, which project to the central nucleus, which projects to areas for freezing, blood pressure and hormones sent out
What are the Htr-2a neurons in the central amygdala important for and where do they project?
feeding and the brainstem - When activated, the food consumption is increased in mice.
The central amygdala has previously been seen as a relay station, but newer studies show that it’s?
important for freezing
the central amygdala projects to?
modulatory areas, the hypothalamus and the PAG
important cells in the central amygdala
SOM, PKC-delta and CRF cells, which are implicated in freeze and flight
There is a reciprocal inhibitory relationship between the Htr-2a and ??? cells
There is a reciprocal inhibitory relationship between the Htr-2a and PKC-delta cell
Instead of being a passive relay, the central amygdala is more like?
an integrator that uses state depended inputs from many regions of the brain and computes a scaled output (can vary in magnitude).
is the central amygdala plastic?
Yes, and experiences can change it’s connections
PAG
The PAG received strong projections from the central amygdala. It’s in the midbrain and is like a column around the ventricle. Many studies have shown that the different part of the PAG are functionally different.
The ventrolateral PAG is important for?
freezing
The dorsolateral PAG is important for?
flight
PAG and pain
The PAG is also part of the ascending and descending pain pathway (can be analgetic during a threatening situation). The PAG is part of the descending branch that controls heart functions (it regulated the parasymp and symp inputs)
The complexity of anxiety
Anxiety is a state, and thinking of it like so will allow us to look at pathological versions of anxiety more flexible. Being anxious is not a disease, it’s a defense mechanism. Nonetheless, it can be a problem when it becomes maladaptive. The stimuli and the circuits for different types of anxiety. E.g. Phobia can be triggered visually with a strong sensory component. For panic disorder, a peripheral dysfunction might trigger a response and so on.
