CSB332 Lecture 17 Notes

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Cell and Systems Biology
Francis Bambico

CSB332 Lecture 17 Slide 7 - 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 relax. 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). Slide 10 - 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 humans.  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 human patients.  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 in animals. 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 (e.g., BDNF)  Post-mortem studies in human patients show decreased BDNF expression in key limbic structures (e.g., prefrontal cortex, hippocampus).  Electrophysiology o Extracellular recording  Find changes in the AP firing pattern (e.g., dorsal raphe nucleus)  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.  Two-photon microscopy o Look for changes in the density of synapses in discrete regions of the brain Slide 11 - 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 Slide 12 - 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. Slide 13 - 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 cerebral cortex. 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. Slide 14 - 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
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