CSB332 Lecture 17
- When stress is chronic, you can’t have any sort of control over the stressors.
- What signals from the environment signal the dorsal medial part of the cerebral cortex? The
dorsal medial cortex is analogous to the dorsal part of the medical prefrontal cortex in rodents.
It has been shown to be involved in our ability to have a sense of control and predictability of
the stressors that we experience. When the dorsal medial prefrontal cortex doesn’t get to
process this information and if there’s too much information, then the dorsal medial prefrontal
cortex could tell you to stop (e.g., you cannot overcome these stressors anymore; you have to
do something about it). This is when you experience symptoms. The symptoms that you
experience are tell-tale signs that the dorsal medial prefrontal cortex is telling you to stop and
o The dorsal medial prefrontal cortex is affected in depression.
o The dorsal medial prefrontal cortex tells your body that your resources are not sufficient
in response to unpredictable and uncontrollable stressors. People who don’t respond to
the symptoms would eventually experience psychiatric disorders.
- If the stressors are moderate and the dorsal medial prefrontal cortex understands that you have
the resources to easily address the stressor, then you can easily habituate, especially if the
stressors are predictable and controllable. Habituation is mediated by the endocannabinoid
system (e.g., 2-AG).
- If the stressors are chronic and unpredictable, then you don’t give your body to habituate. The
demands of the HPA axis cannot be addressed properly, so you are unable to habituate from
these stressors, which results in problems (e.g., PTSD).
- How would you investigate the neurophysiological changes associated with depression?
o fMRI or PET
o Post-mortem studies that outline the volume of gray matter in different parts of the brain
o Post-mortem counts of cell markers or neurons in different parts of the brain
o Animal models
Use animal models that exhibit behaviours that are analogous to depression in
There is predictive validity if the behaviours that you see in an animal
can be alleviated by the administration of anti-depressants. If the
behaviours are prevented by anti-depressants, then this would seem to
be similar to the behaviours that anti-depressants are preventing in
There is face validity if the behaviours that you observe in the animals
at surface level are similar to what you see in human depressed
patients. The symptoms in human depressed patients can be modeled
o A simple model of anhedonia, which is a core symptom in
depression, is the progressive decrease in the intake of
palatable food/solution in animals that have been pre-exposed to chronic stress. Chronic stress is a pre-disposing factor to
developing depressive-like states.
If you see behavioural changes in the animal models with high predictive validity
and high face validity and high construct validity, then you can:
Ex vivo assay
o Remove the brain from the depressed animal models
o Run neurobiological assay to examine changes in protein levels
Post-mortem studies in human patients show decreased
BDNF expression in key limbic structures (e.g.,
prefrontal cortex, hippocampus).
o Extracellular recording
Find changes in the AP firing pattern (e.g., dorsal raphe
Depressive disorders have been linked with a decrease
in the activity of the dorsal raphe nucleus. 5-HT is
implicated in depression.
Chronically stressed animals exhibit a lower firing rate.
There is impairment in the molecular machinery of the
neurons that regulate firing activity patterns. There is a
decrease in the number of neurons that you would be
able to record from.
You have to distinguish which ones are
serotonergic neurons because not all of the
neurons will be serotonergic.
Other brainstem nuclei are also affected. There is also
an increase in the firing rate of noradrenergic neurons.
o Look for changes in the density of synapses in discrete regions
of the brain
- This is a two-photon microscopic image of dendrites of pyramidal neurons in the prefrontal
cortex of control animals controlled to chronically stressed animals.
o Thinning of the dendritic branch
o Decrease in number of dendritic spines
Decrease in the number of synaptic projections/inputs
Decrease in the number of synapses
- You can conduct ex vivo assay to tell you changes in the levels of proteins that are related to
depression. If there is a decrease in number of dendritic spines and a decrease in synaptic
contacts from two-photon microscopic images, then you expect to find a decrease in the levels
of synaptic proteins. A decrease in synapse associated proteins means that there will be a
decrease in synaptic contact. - Western blot analysis measures the level of the synapse associated proteins. You see a
significant decrease in synapsin I. Synapsin I is a synapse associated protein located within the
presynaptic membrane that functions to anchor the synaptic vesicles on the cytoskeleton.
Synapsin I holds the synaptic vesicles in place in the presynaptic membrane.
- PSD-95 is another example of a synapse associated protein. It is located on the postsynaptic
membrane. In neurons, it makes up the multimeric scaffolding necessary for the clustering of
receptors (e.g., GluR1). PSD-95 is a counterpart of rapsyn in the muscle fiber. A counterpart of
PSD-95 in the NMJ or the motor end plate is rapsyn, which aggregates or anchors cholinergic
receptors to the cytoskeleton of muscle fibers.
- What are the molecular events that cause these disturbances in the brain? Once you’ve
identified the changes in the brain of depressive animals, then the next step is to identify what
causes these changes and what causes the synaptic degeneration.
- There are a number of molecular events associated with synaptic changes in chronic stress and
depression. This implicates two families of receptors that interact with each other and controls
the activity patterns of many types of neurons in the cerebral cortex.
- Glutamatergic receptors play an important role in the synaptic integrity of neurons in the
o There are two types of glutamatergic receptors in the brain.
Ionotropic glutamate receptors
AMPA receptor is activated by glutamate and AMPA
o AMPA is a synthetic analog of glutamate
Kainate receptor is activated by glutamate and kainate acid
NMDA receptor is activated by glutamate and NMDA
Metabotropic glutamate receptors are coupled to G proteins
- The molecular receptors that mediate the effects of glucocorticoids and stress hormones are GR
and MR. They are both activated by corticosterone in rodents, and cortisol or glucocorticoids in
humans. The difference is that MR has a higher affinity (10-fold) to corticosterone, and GR have
lower affinity. Therefore, stress is a result of overactivation in response to severe stressors, or
an increase in the activity of stress hormones (e.g., glucocorticoids). As a result of increased
hyperactivation, you are not only activating MR, but you are also recruiting GR. This is an
indication that stress is too much because you are exceeding a certain amount of glucocorticoids
in the brain that you are not only activating the MR but also GR. GR has lower affinity, but if
there is too much stress hormones in the brain, then you will activate GR as a response to the
overproduction of glucocorticoids or the increase in the synaptic activity of glucocorticoids.
- This is how GR and different members of glutamate receptors interact in the release of
glutamate. GR are mainly localized on the presynaptic membrane. Glutamate receptors (both
AMPA and NMDA receptors) are mainly expressed on the postsynaptic neuron.
- EAAT are expressed in the postsynaptic neuron and glial cells. EAAT re-uptake and recycle
glutamate. Once glutamate has performed its action in the synaptic cleft, then glutamate is