farmaco pt1

Rwy'n gobeithio y byddwn yn gweithio'n fawr iawn, ond rwy'n gobeithio y byddwn yn gweithio'n fawr iawn, ond rwy'n gobeithio y byddwn yn gweithio'n fawr iawn, ond rwy'n gobeithio y byddwn yn gweithio'n fawr iawn, ond rwy'n gobeithio y byddwn yn gweithio'n fawr iawn, ond rwy'n gobeithio y byddwn yn gweithio'n fawr iawn, ond rwy'n gobeithio y byddwn yn gweithio'n fawr iawn, ond rwy'n gobeithio y byddwn yn gweithio'n fawr iawn, ond rwy'n gobeith gobeithio y byddwn yn gweithio'n fawr iawn, ond rwy'n gobeithio y byddwn yn gweithio'n fawr iawn, ond rwy'n gobeithio y byddwn yn gweithio'n fawr iawn, ond rwy'n gobeithio y byddwn yn gweithio'n fawr iawn, ond rwy'n gobeithio y byddwn yn gweithio'n fawr iawn, ond rwy'n gobeithio y byddwn yn gweithio'n fawr iawn, ond rwy'n gobeithio y byddwn yn gweithio'n fawr iawn, ond rwy'n gobeithio y byddwn yn gweithio'n fawr iawn, ond rwy'n gobeithio y byddwn yn gweithio'n fawr iawn, ond rwy'n gobeithio y byddwn yn gweithio'n fawr iawn, ond rwy'n gobeithio y byddwn yn gweithio'n fawr iawn, ond rwy'n gobeithio y byddwn yn gweithio'n fawr iawn, ond rwy'n gobeithio y byddwn yn gweithio'n fawr iawn, ond rwy'n gobeithio y byddwn yn gweithio'n fawr iawn, ond rwy'n gobeithio y byddwn yn gweithio'n fawr iawn, ond rwy'n gobeithio y byddwn yn gweithio'n fawr iawn, ond rwy'n gobeithio y byddwn yn gweithio'n fawr iawn, ond rwy'n gobeithio y byddwn yn gweithio'n fawr iawn, ond rwy'n gobeithio y byddwn yn gweithio'n fawr iawn, ond rwy'n gobeithio y byddwn yn gweithio'n fawr iawn, ond rwy'n gobeithio y byddwn yn gweithio'n fawr iawn, ond rwy'n gobeithio y byddwn yn gweithio'n fawr iawn, ond rwy'n gobeithio y byddwn yn gweithio'n fawr iawn, ond rwy'n gobeithio y byddwn yn gweithio'n fawr iawn, ond rwy'n gobeithio y byddwn yn gweith yn fawr iawn, ond rwy'n gobeithio y byddwn yn gweithio'n fawr iawn, ond rwy'n gobeithio y byddwn yn gweithio'n fawr iawn, ond rwy'n gobeithio y byddwn yn gweithio'n fawr iawn, ond rwy'n gobeithio y byddwn yn gweithio'n fawr iawn, ond rwy'n gobeithio y byddwn yn gweithio'n fawr iawn, ond rwy'n gobeithio y byddwn yn gweithio'n fawr iawn, ond rwy'n gobeithio y byddwn yn gweithio'n fawr iawn, ond rwy'n gobeithio y byddwn yn gweithio'n fawr iawn, ond rwy'n gobeithio y byddwn yn gweithio'n fawr iawn, ond rwy'n gobeithio y byddwn yn gweithio'n fawr iawn, ond rwy'n gobeithio y byddwn yn gweithio'n fawr iawn, ond rwy'n gobeithio y byddwn yn gweithio'n fawr iawn, ond rwy'n gobeithio y byddwn yn gweithio'n fawr iawn, ond rwy'n gobeithio y byddwn yn gweithio'n fawr iawn, ond rwy'n gobeithio y byddwn yn gweithio'n fawr iawn, ond rwy'n gobeithio y byddwn yn gweithio'n fawr iawn, on o'r sefyllfa y mae'n ei ddweud, mae'n anodd iawn, anodd iawn. Ar y dechrau, rydyn ni'n cael y hybogaeth ynglyn â'r hyn y mae'r wirioneddwyr yn ysgrifennu y gynhyrchiadau o lefelau llawer o ddiddordeb, sy'n ymwneud â llinellau llawer, ac felly dod o'r adnoddau bod y gynhyrchiadau sy'n cael ei ddefnyddio yn y 50au o'r blynedd diwethaf fel gynhyrchiad anti-diddordeb, gynhyrchiad anti-hypertensiol, oherwydd roedd yn gallu ddefnyddio gynhyrchiadau llawer. Rydyn ni'n gwybod yn dda nad ydyn ni'n defnyddio unrhyw gynhyrchiadau arall, ond rydyn ni'n cael gynhyrchiadau cyffredin, cyffredin cyffredin cyffredin, ac yn benodol, mae'r datblygu o'r gynhyrchiadau a'r gynhyrchiadau cronig yn eu defnyddio. Er enghraifft, ym Mhrydain, er enghraifft, y gynhyrchiadau, nid y gynhyrchiadau, ond y gynhyrchiadau ddod o'r rhan o'r gynhyrchiad sy'n cael ei ddefnyddio o'r gynhyrchiadau a'r gynhyrchiadau, yng Nghymru, yng Nghymru, y gynhyrchiadau a'r gynhyrchiadau a'r gynhyrchiadau a'r gynhyrchiadau a'r gynhyrchiadau a'r gynhyrchiadau a'r gynhyrchiadau a'r gynhyrchiadau a'r gynhyrchiadau a'r gynhyrchiadau a'r gynhyrchiadau a'r gynhyrchiadau a'r gynhyrchiadau a'r gynhyrchiadau a'r gynhyrchiadau a'r gynhyrchiadau a'r gynhyrchiadau a'r gynhyrchiadau a'r gynhyrchiadau a'r gynhyrchiadau a'r gynhyrchi Yn gyffredinol, mae'r ffeintiwm debygol, mae'n cael ei ddefnyddio i ddefnyddio'r gynhyrchiadau o'r gynhyrchiadau a'r gynhyrchiadau o'r gynhyrchiadau o'r gynhyrchiadau o'r gynhyrchiadau o'r gynhyrchiadau o'r gynhyrchiadau o'r gynhyrchiadau o'r gynhyrchiadau o'r gynhyrchiadau o'r gynhyrchiadau o'r gynhyrchiadau o'r gynhyrchiadau o'r gynhyrchiadau o'r gynhyrchiadau o'r gyn ry'n ni'n gwybod ei fod yn gallu gwblhau'r gynhyrchiadau cyffredinol o'r mononin yn y terminau gynhyrchol, ac mae hynny'n golygu bod, ar un pwynt cyfnodol, ganddyn ni'r gynhyrchiadau sy'n aml o'r gynhyrchiadau gynhyrchol, oherwydd mae'r gynhyrchiad yn cael ei gwblhau, ac felly nid yw'r penyntin, nid yw'r mononin, yn gyffredinol, yn gallu ei ddiflannu gan y gynhyrchiadau cyffredinol. Felly, mae'n anodd ddefnyddio'r penyntin, felly mae'n anodd ddefnyddio'r gynhyrchiadau cyffredinol. Iawn. Felly, ar y gynhyrchiad hwn, roeddem yn cael ei gysylltu â'r teori sy'n gweithio gyda'r hyfforddiant mononin. Felly, maen nhw'n dweud, iawn, mae'r gynhyrchiad yn canolbwyntio ar yr effeithiolaeth, ar y gynhyrchiad mononin, ac yna mae'n canolbwyntio ar yr effeithiolaeth mononin hefyd. Ac, oherwydd bod y pwyso'n cael ei ddefnyddio gan ddiflannu, ac mae'r pwyso'n cael ei gysylltu â'r rhan fawr o'r gynhyrchiad, mae'r pwyso hwn, sy'n mania, mae'n rhaid iddyn nhw gael ei ddefnyddio gan ddiflannu'r effeithiolaeth mononin hwn. Mae'r mania hwn mewn rhan fawr o'r gynhyrchiad mononin. Felly, fel y gallwch chi ysgrifennu, mae hwn mewn gwirionedd yn amlwg o'r sefyllfa. Felly, mae'n amlwg o mononin, mae'n amlwg o mononin yn yr effeithiolaeth mononin, mae'n amlwg o mononin yn yr effeithiolaeth mononin yn y sefyllfa ddiflannu'r effeithiolaeth mononin. Erbyn hynny, yn ogystal â'r sefyllfa hwnnw, mae'r pwyso'n gallu llunio'r bobl, mae'r pwyso'n gallu llunio'r bobl, ac nid oes unrhyw adnodd, ac nid oes unrhyw adnodd, mae'r pwyso'n gallu llunio'r pobl, ac nid oes unrhyw adnodd, mae'r pwyso'n gallu llunio'r pobl, ac nid oes unrhyw adnodd, mae'r pwyso'n gallu llunio'r pobl, ac nid oes unrhyw adnodd, mae'r pwyso'n gallu llunio'r pobl, ac nid oes unrhyw adnodd, mae'r pwyso'n gallu llunio'r pobl, ac nid oes unrhyw adnodd, mae'r pwyso'n gallu llunio'r pobl, ac nid oes unrhyw adnodd, mae'r pwyso'n gallu llunio'r pobl, ac nid oes unrhyw adnodd, mae'r pwyso'n gallu llunio'r pobl, ac nid oes unrhyw adnodd, mae'r pwyso'n gallu llunio'r pobl, ac nid oes unrhyw adnodd, mae'r pwyso'n gallu llunio'r pobl, ac nid oes unrhyw adnodd, mae'r pwyso'n gallu llunio'r pobl, ac nid oes unrhyw adnodd, mae'r pwyso'n gallu llunio'r pobl, ac nid oes unrhyw adnodd, mae'r pwyso'n gallu llunio'r pobl, ac nid oes unrhyw adnodd, mae'r pwyso'n gallu llunio'r pobl, ac nid oes unrhyw adnodd, mae'r pwyso'n gallu llunio'r pobl, ac nid oes unrhyw adnodd, mae'r pwyso'n gallu llunio'r pobl, ac nid oes unrhyw adnodd, mae'r pwyso'n gallu llunio'r pobl, ac nid oes unrhyw adnodd, mae'r pwyso'n gallu llunio'r pobl, ac nid oes unrhyw adnodd, mae'r pwyso'n gallu llunio'r pobl, ac nid oes unrhyw adnodd, mae'r pwyso'n gallu llunio'r pobl, ac nid oes unrhyw adnodd, mae'r pwyso'n gallu llunio'r pobl, ac nid oes unrhyw adnodd, mae'r pwyso'n gallu llunio'r pobl, ac nid oes unrhyw adnodd, mae'r pwyso'n gallu llunio'r pobl, ac nid oes unrhyw adnodd, nid oes unrhyw adnodd, nid oes unrhyw adnodd, nid oes unrhyw adnodd, nid oes unrhyw adnodd, nid oes unrhyw adnodd, nid oes unrhyw adnodd, nid oes unrhyw adnodd, nid oes unrhyw adnodd, nid oes unrhyw adnodd, nid oes unrhyw adnodd, nid oes unrhyw adnodd, nid oes unrhyw adnodd, nid oes unrhyw adnodd, nid oes unrhyw adnodd, nid oes unrhyw adnodd, nid oes unrhyw adnodd, nid oes unrhyw adnodd, nid oes unrhyw adnodd, nid oes unrhyw adnodd, nid oes unrhyw adnodd, nid oes unrhyw adnodd, nid oes unrhyw adnodd, nid oes unrhyw adnodd, nid oes unrhyw adnodd, nid oes unrhyw adnodd, nid oes unrhyw adnodd, nid oes unrhyw adnodd, nid oes unrhyw adnodd, nid oes unrhyw adnodd, nid oes unrhyw adnodd, nid oes unrhyw adnodd, nid oes unrhyw adnodd, nid oes unrhyw adnodd, nid oes unrhyw adnodd, nid oes unrhyw adnodd, nid oes unrhyw adnodd, nid oes unrhyw adnodd, nid oes unrhyw adnodd, nid oes unrhyw adnodd, nid oes unrhyw adnodd, nid oes unrhyw adnodd, nid oes unrhyw adnodd, nid oes unrhyw adnodd, nid oes unrhyw adnodd, nid oes unrhyw adnodd, nid oes unrhyw adnodd, nid oes unrhyw adnodd, nid oes unrhyw adnodd, nid oes unrhyw adnodd, nid oes unrhyw adnodd, nid oes unrhyw adnodd, nid oes unrhyw adnodd, nid oes unrhyw adnodd, nid oes unrhyw adnodd, nid oes unrhyw adnodd, nid oes unrhyw adnodd, nid oes unrhyw adnodd, nid oes unrhyw adnodd, nid oes unrhyw adnodd, nid oes unrhyw adnodd, nid oes unrhyw adnodd, nid oes unrhyw adnodd, nid oes unrhyw adnodd, nid oes unrhyw adnodd, nid oes unrhyw adnodd, nid oes unrhyw adnodd, nid oes unrhyw adnodd, nid oes unrhyw adnodd, nid oes unrhyw adnodd, nid oes unrhyw adnodd, nid oes unrhyw adnodd, nid oes unrhyw adnodd, nid oes unrhyw adnodd, nid oes unrhyw adnodd, nid oes unrhyw adnodd, nid oes unrhyw adnodd, nid oes unrhyw adnodd, nid oes unrhyw adnodd, nid oes unrhyw adnodd, nid oes unrhyw adnodd, nid oes unrhyw adnodd, nid oes unrhyw adnodd, nid oes unrhyw adnodd, rydyn ni'n cael niferoedd sy'n y hipotezaeth receptorol, felly gwybod bod yn rhanbaratof o'r adnodd o'r sgwrs adnodd, ond mewn gwirionedd roedd yn brosiect o'r adnodd yn benodol, mae'r adnodd yn un o'r ardalau mwyaf bwysig ynglyn â'r adnodd receptorol yw'r sgwrs, yn benodol yw'r sgwrs cyffredinol. Ac rydyn ni'n dweud hynny, efallai ein bod ni'n cael ysgrifennu'r cwestiwn, ac rydyn ni'n meddwl am yr adnodd o'r adnodd, ond rydyn ni'n meddwl am'r cwestiwn. Felly, yn y cwestiwn, rydyn ni'n cael rhywfaint o adnodd neu'r adnodd, ond, a'r rhan fwyaf o'r adnodd neu'r adnodd, rydyn ni'n meddwl am yr adnodd rydyn ni'n meddwl am yr adnodd rydyn ni'n meddwl am yr adnodd rydyn ni'n meddwl am yr adnodd a'r adnodd a'r adnodd a'r adnodd a'r adnodd a'r adnodd a'r adnodd a'r adnodd a'r adnodd a'r adnodd a'r adnodd a'r adnodd a'r adnodd a'r adnodd a'r adnodd a'r adnodd a'r adnodd a'r adnodd a'r adnodd a'r adnodd a'r adnodd a'r adnodd a'r adnodd a'r adnodd a'r adnodd a'r adnodd a'r adnodd a'r adnodd a'r adnodd a'r adnodd a'r adnodd a'r adnodd a'r adnodd a'r adnodd a'r adnodd a'r adnodd a'r adnodd a'r adnodd a'r adnodd a'r adnodd a'r adnodd a'r adnodd a'r adnodd a'r adnodd a'r adnodd a'r adnodd a'r adnodd a'r adnodd a'r adnodd a'r adnodd a'r adnodd a'r adnodd a'r adnodd a'r adnodd a'r adnodd a'r adnodd a'r adnodd a'r adnodd a'r adnodd a'r adnodd a'r adnodd a'r adnodd a'r adnodd a'r adnodd a'r adnodd a'r adnodd a'r adnodd a'r adnodd a'r adnodd so the problem was that also related to this that something was not was not enough in this vision of a deficiency in this neurosensitivity level was that the plastic drugs that are increasing the level of this neuramine increasing the level of norepinephrine and serotonin if this is actually the cause of depression taking this drug we will have immediately the increase in the amount of this neurotransmitters and thus we expect an immediate effect but that was not the case and clinicians know very well that when they prescribe a drug for depression in order to gain the first benefit from this therapy, patients need to take it at least for 3-4 weeks so the effect is not immediate they have to wait sometimes some weeks actually, maybe one month before having benefit from the treatment and thus this means that probably the alteration in the level is not actually the real problem but it's something probably it is the starting point and so this is why they said probably we have alteration in neuroplasticity and we need with our drug to imbue let's say a crucial balance of this altered neuroplasticity and one of the first things they suggested was probably when we we have our patients that is anyway described by low amount of neurotransmitters and increased amount of sensitivity of depression this is the starting point when the patient arrives to the to the clinician to the psychiatrist then we have the restriction of the medication and I told you that the classical compound increase the amount of neurotransmitters mainly and so we have the medication introduced here and this is compound first of all increase the amount of neurotransmitters because usually I told you the mechanism of action of the antidepressant they block the neurotransmitters ok so we have an increase of the amount of neurotransmitters in the synapses and this is for that but actually why this increase in the amount of neurotransmitters is not enough to induce the antidepressant effect, why? because it is just a starting point, the trigger of a series of modifications in the therapy that probably play a more important role in the therapy in the beneficial effect and for example increasing the amount of neurotransmitters induce a further modification in the receptor level you know very well that when we have an excess of neurotransmitters we have usually in healthy physiological situation a decrease in the amount of receptors because if you have a lot of neurotransmitters when we have a lot we increase the amount of receptors when we have an excess of neurotransmitters we decrease the amount of receptors so the medication are inducing an excess of neurotransmitters and thus this triggers a modification in the amount of receptors so the receptor decreases and when we have this event this increase in the receptor, this increase in the amount we start to have the beneficial effect the clinical effect of this compound so this means that actually this compound so the immediate effect of the compound is not let's say what is what is important in depression but it's just the starting point and we have a series of events that we need in order to regain the original balance that has been lost due to this disorder in the circuitry this is just another thing that suggests that this modification in the circuitry is important I think also that the time course of receptor adaptation we are in the brain after taking the medication is consistent not only with the clinical effect that I told you but also with the development of tolerance to side effects if side effects are due to the increased amount of neurotransmitters in different circuitries, you know that this compensation has occurring in every circuitry and so in the let's say healthy circuitries that are overstimulated by this effect on neurotransmitters we have also the compensation that reduction in receptors and so we have the tolerance so disappearing with a reduction in the side effects so apparently this is this is true to explain what is going on but probably it is not only a problem of receptors we do not have to focus our attention on the receptors and so on there is a lot of events that occur after the receptor stimulation and the activation so let's say that the father said he was not only to look at the receptors but he focused the attention on the pathways that are triggered by those receptors and their activation and for example we know that according to the activation of the mononuclear receptors we have for example the activation of some pathways that are able to activate the transcription in the nucleus of some genes and among the genes that apparently are activated there is CTNF CTNF is brain-derived neurotrophic factor it is a neurotrophic factor that plays a very very important role in the health of the brain in the health of the human neurons and the circuitry so it is very very important for neuronal survival for neurogenesis we know that in the adult brain we have in the human brain at least one area in which we still have neurogenesis the hippocampus the dental chart of the hippocampus we have also let's say this is still debated but in rodents it has been shown neurogenesis also in the subventricular zone in the frontal zone and where we have the migration into the vascular zone this is probably most important for rodents for macrosmeat and most of the time we are micro or nato and probably this is not such an important event but I think that a little bit of this event is still present in the in the human brain because I lost my brain in 2015 after a very intense cold for spring and I after walking around I had this really intense cold and I was not able to remove it, to smell anything for at least 6 months then I started regaining the smell but a little bit and even now I have some smells that are not as the original ones, for example coffee I remember that I had a sensation a specific smell of coffee that I cannot count anymore ok and so there are also some other smells that I I haven't recovered but let me put this book because whenever I cook cauliflower I cannot smell it ok and so everything that has a specific component I cannot catch and this is a problem because gas is adjusted in order to catch your attention whenever you have a leakage of gas ok and remember I had something like that 5 years ago in the house in the mountains and I wasn't able to smell anything, luckily there were my children with me and they warned me about that ok so there is probably it is very very low the level of neurogenesis but anyway PDNF is very very important for neurogenesis for neuroplasticity because the synaptic genesis and the modification of the cortex space is driven by PDNF so PDNF growth factors are important and of course what now we know of course let's say that starting from the beginning of the second millennia we had a lot of research regarding PDNF and how environmental situation may move in PDNF production in the brain and now we know that PDNF is affected by stress for example by alteration in the microbiome by chronic medical illnesses, by alteration in the sleep factor by events of inflammation, neuroinflammation and also by birth and death all these events, alteration in these events can these events and alteration can decrease the production of PDNF and decrease in the production of PDNF can modify the plasticity of the brain plasticity and this represents very very important let's say risk factors risk factors and this is a cartoon that I like it's a little bit for kids but if we do not have PDNF that is important water to keeping in life our neurons at the end of the day we have the life of neurons neurons die neurons die because of chronic diseases induced by blood instead if everything is going in the right way we have the normal amount, the proper amount of PDNF that is important to keep our neurons alive and actually with a very very development between our projections and and accordingly apparently this is what is probably going on in the brain of people suffering from depression because thanks to the brain imaging approaches in a human being scientists were able to observe actually as between each web specifically in this area, do you know in the human brain what is present in this area? the hippocampus ok, the hippocampus is present here and through brain imaging so magnetic resonance specifically scientists were able to describe a reduction in the volume of the hippocampus in the breast patient and also a reduction in this is the dendritic spine ok so the magnetic contact that we may have in the in our hippocampus and these are the dendritic spine in the breast patient as you can see we have a decrease in spine we have a decrease in spine which means that we have a decrease of sensitivity so not only the research in animal models has described a situation like that in this model from the breast but also brain imaging in human patients suffering from depression has suggested the presence of reduction in the hippocampus volume and also a reduction in the dendritic spine in the hippocampus of the breast patient and let's say that I told you that at the beginning of the second millennium there was this research going on and in 2006 appeared a paper by Ron and Lisa Montagia of the most important neuropsychiatry clinical and clinical neuropsychiatry in the world and they suggested a new approach model for breast related disorders because when we think about depression we will see we have seen that most of the events triggering a depressive episode are related to an increased amount of stress suffered by the population ok and so they said also that the hippocampus was the key point the key brain area in which something was going on during the excess of stress suffered by the patient what happened? why the hippocampus is such an important point? because it has extensive connections with the amygdala and we know very well that the amygdala is the brain region where we have the full control of emotion and fear anxiety for example ok moreover the hippocampus also has extensive projection and physical contact that we know that is very very important for cognition and memory ok working memory, cognition in general mood in general ok so whenever we have abnormalities in the hippocampus and it can imagine these abnormalities these only functionalities also abnormal functionalities can reverberate into the amygdala and into the frontal cortex affecting those surfaces controlling emotion, fear cognition, mood that is controlling all the symptoms that we have described present in the frustration and moreover the hippocampus itself is very very important for memory, we know very well for cognition in general anxiety it is very very important in the control of the activity of the HPA axis hypothalamic ventricular artery and why stress why stress is the is playing such an important role in triggering the action because stress stress is able to increase the the release because of this activation of the HPA axis of glucocorticoid ok and glucocorticoid, the increasing glucocorticoid decreases the production of TPNF and if we have a decreasing TPNF this is what happens at the neurons we have described before in the hippocampus, look here this is the L2 neuron this is the dendritic stream that finds in the L2 neuron this is what is present after this excessive glucocorticoid, think about the chronic release of glucocorticoid and that chronic decrease in the release of TPNF we have an atrophy of our neurons we have a decreased survival of these neurons if you look at neurogenesis in the hippocampus, this is decreased and this means that an increased vulnerability to the depressive and on the other way around when we treat patients with compounds able to increase the levels of more energy and serotonin what we have in patients we have been studied in animal we have an increase in TPNF in the hippocampus, we have an increase in neurogenesis we have an increase let's say not an increase but a recover of the of the growth of neurons so neurons regain their healthy dendritic stream with a lot of spines ok, so this is the what happens in the hippocampus is very very important so it is a key in the relation moreover there is a very important connection between the hippocampus and the HPA axis and the HPA axis the HPA axis plays a very important role because this regulation in the HPA axis may contribute to depression and neurodegeneration that has been observed in the patient let's do another step further ok, why TPNF the hippocampus in the healthy, this is the healthy brain ok, in the healthy brain you know that every day we may have a stress situation which is something that we can cope with usually a little bit of stress is useful because it's good for our performance it's good for our ability to perform in everyday life just a little bit too much stress is not good just a little bit, let's see what does, just a little bit of stress, just a little bit of stress activates the HPA axis, however the hippocampus is usually able to come to tone down the activation of the HPA axis because the hippocampus and URF the amygdala are able to tone down the activation of the hypothalamus the hypothalamus is less activated it will have less TRF TRF is the corticotropin release factor that is the compound that is able to activate the hippocampus if I have less activation I will have less stimulation of the hippocampus and thus less release of ATPH that is the compound to activate the adrenal glands and to induce the production of glucocorticoids so the amygdala and the hippocampus in the healthy brain are able to tone down this system so we have stress that increases glucocorticoids but we can control that what happens instead in the brain of people suffering from depression the hippocampus we have seen in the hippocampus so the hippocampus and the amygdala is more able to tone down the hypothalamus ok and thus the hypothalamus will release a lot of TRF that will stimulate a lot of triglycerides to activate ATPH ATPH will induce the adrenal glands to produce an increased amount of glucocorticoids and usually in the healthy brain in the healthy brain we have also negative feedback controlled by glucocorticoids on the activity of the hypothalamus so it's too much glucocorticoids are present they are also able to inhibit their own production instead in the depressive brain with low visibility this negative feedback control is lost and thus as you can imagine we have this alteration in the functionality of the HPA axis and accordingly this alteration in the functionality of the HPA axis has been long described in the presentation and also the sensitivity to the feedback look here these are the plasma cortical cortical levels in depressed patients psychiatric controlled and normal controlled as you can see we have some patients depressed patients that have let's say normal amount of cortical as the other patients suffering from other disorders or even the normal control however we have more of the depressed patients that have increased amount of cortical levels suggesting that this function in the functionality of the HPA axis moreover look here cortisol in a healthy people in a healthy brain is usually secreted according to a circadian rhythm because cortisol activates us this is why a little bit of stress is good because it is able to activate us usually look here we have increased cortisol amount during the early morning and then at midday start decreasing and decrease during the night and start increasing in the early morning ok look here in depressed patients they have higher cortical levels and this higher cortical levels also lose this rhythmicity it is less evident in depressed patients the rhythmicity of the production of cortisol and moreover again in depressed patients we do not have the negative feedback inhibition the feedback inhibition and for example if I inject the zametazone cortisol in healthy people I have immediately a reduction in the production of cortisol because I have a higher amount from the cortisol instead look at what happens in depressed patients when I inject the I have an initial decrease but this is not comparable with what we have in healthy people ok we have significant reduction in this feedback inhibition ok so this is to say that actually in depressed patients the HPA axis functionality is significant and before the break let me introduce you another thing what has been demonstrated in the recent years again we are in the second period ok is that the endocannabinoid system plays a very important role in stress this is one of the most important roles probably of the endocannabinoid system because it is a buffer of stress ok and usually when we have a stress test in your test in the amygdala we have due to the we have an increase in the production of FAM FAM is the degravity of enzyme of anandamide one of the two most important endocannabinoid systems if I have an increase in the degravity of enzyme it means that I have an important reduction in anandamide amount so after the at the very beginning of the stress episode I have a decrease in anandamide level and this decrease in anandamide in anandamide level allow the manifestation of the symptoms of stress because usually anandamide is able to tone down the stress high levels of anandamide means less stress, less anxiety for the person however and this is very rapid because at the very beginning the decrease in anandamide allow the manifestation of the stress episode, of the symptoms of the activation this is chronologically relevant but at a certain point later on we will have instead an increase in the other endocannabinoid the 2-acetamidritol the 2-HG ok and this increase in 2-HG is fundamental for the termination of the stress episode ok so this situation of the amount of the 2 main endocannabinoids is important for what we call the stress response, for what happens physiologically in our system under stress ok, at the beginning the decrease in anandamide is needed to allow the manifestation of stress ok, but we have a physiological situation we have to stop the stress response, because we know very well that if stress goes on we have a chronic situation that is deleterious for our system so we have to stop the stress response and to stop it we increase the amount of 2-HG ok so and accordingly whenever we decrease the amount of anandamide even in our animal model that we have an increase in anxiety an increase activation of the HPA axis, an increase in neurogenesis, an increase in peer extinction we have the occurrence of amygdonia and this is something that is a little bit debated because it depends on the specific situation, we may have an increase in memory consolidation but in memory consolidation about fear situations so this is the last one and instead the increase in 2-HG the delayed one, is able to stop the alteration in the HPA axis response mostly this is very very important 2-HG because of its ability to reduce LPD and decrease memory retrieval this is true I again point something that we will do in the future lesson this is a disorder that is caused by an excessive memory retrieval which like a one does, it can cause traumatic stress and disorders characterized by an excess of memory retrieval, 2-HG is fundamental to decrease this memory retrieval we have to forget 2-HG we have to retain them in order to avoid future dangerous situations but this ability to retain some experiences should not become an obstruction an obstruction is in 2-HG people can not forget those specific experiences so 2-HG this is useful ok and then of course this is the development of all the observations that is is there a role for generation of memory system in the creation of autonomous memory and accordingly again in 2011 2011 2015 we have this paper which revealed that probably the endocannabinoid system plays a role in the theology of depression and thus there was a lot of research in relation to the pharmacological exploration of this system which set up a new treatment for depression but we were not so lucky because of the many effects of 2-HG of the many effects of this system there was a compound that was an inhibitor of the far enzyme the degradative enzyme of anandamide that arrived in clinical trials phase 2 or did not pass phase 1 because it was actually very successful in animal models but when toxicity was dying in humans it was shown to accumulate in the liver and so there was a possibility to cause liver toxicity and so it was shown unfortunately ok 5 minutes of rest and then we can go ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ...