The Antidepressant Effects of Lactate

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Pierre Magistretti discusses how lactate acts on the brain to counter depression.

Institution: King Abdullah University of Science and Technology

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Pierre Magistretti discusses how lactate acts on the brain to counter depression.

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Image courtesy of interviewee. September 21, 2022

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This video discusses the role of lactate in metabolism, particularly in relation to brain function, exercise, and depression. It explains that lactate is produced from glucose metabolism in cells and is not simply a waste product; rather, it is shuttled between different cells for energy production. The "astrocyte neuron lactate shuttle" allows glial cells in the brain to produce lactate, which is then used by neurons.

Additionally, during exercise, muscles produce lactate, contributing to the energy exchange within muscle cells and affecting other tissues like the liver and brain. This video emphasizes that lactate is not just a byproduct of metabolism but a significant energy source for cells, especially during physically active states.

This video also connects the production of lactate to its potential antidepressant effects, observing that physical exercise can enhance mood and provide therapeutic benefits against depression. Research indicates that a decrease in glial cells, which produce lactate, correlates with depression, while some antidepressants have been shown to increase lactate levels in these cells.

Experiments demonstrated that injecting lactate into animal models of depression reversed depressive behaviors, unlike pyruvate, which had no such effect. This video indicates lactate may promote neurogenesis—the creation of new neurons in the brain—highlighting its importance in combating the effects of stress and depression.

Overall, the findings suggest that lactate plays a crucial role in energy metabolism and has therapeutic implications for treating depression, particularly through its impact on neurogenesis and the brain's response to stress.

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X-TIMESTAMP-MAP:LOCAL=00:00:00.000,MPEGTS=900000

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Lactate is a product of

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glucose metabolism glucose is the fuel

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for any cell older cells in in the body

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including.

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some of the cells in the brain and so

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glucose is

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transformed to

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a pyruvate and then pyruvate can enter what we

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call oxidation and produce energy

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or some of the pyruvate is transformed

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to lactate and for a long time. It was thought that

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lactating type was a

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An interesting metabolic and product the real molecule

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being pyruvate that then can be burned and

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produce energy.

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Well, it turns out that lactate is not at

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all an end product because it's actually

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exported from cells.

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Taken up by other cells converted back

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to pyruvate and then in produces energy

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in other cells. So

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that's why there are in the body what are

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called lactate shuttles because like it is

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formed in certain cells exported and used

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by other cells. That's a

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general principle that is emerging in Biochemistry.

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And my work over the years showed

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that in the brain this dialogue occurs between

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two cell types lack that

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is produced by glial cells. These are

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no neuronal cells that make up half of

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the brain. These are the cells that mainly take

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up glucose from the blood.

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Converted to lactate and then release it

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for neurons which use it and

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this is called the astrocyte neuron lactate shuttle.

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Now, what does this have to do with the exercise

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and depression? Well during exercise

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muscles produce lactate

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because there is also a shuttle

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there a lactate shuttle that was

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actually initially described by a colleague George

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Brooks at UC Berkeley

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and he showed that

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certain cells in muscles produce lactate

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and other cells other muscle cells

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use lactate. So that's there's a shuttle there

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again.

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And during exercise there is lactate

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that is produced and shuttled

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between the two

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metabolic cells

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the two muscle cells, but then

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there is also lactic that goes into the bloodstream some

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is taken up by the liver.

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And actually the pathway

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goes backwards. So from lack that

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you go back to glucose. It's called gluconeogenesis, but

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also some liked it is remains

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in the circulation and it's taken up by the

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brain and there it can be used

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by neurons.

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Also whenever we move so we

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exercise we we activate brain regions

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whereby glucose enters

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into the brain in those more active

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regions is transformed to lactate by

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this glial cells is astrocytes and

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then lactate is used by by neurons.

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So in a nutshell lactate is

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definitely not a metabolic and product. It's

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actually a very precious metabolic product

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that provides a shackling

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of energy between cells

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And it is produced during exercise in

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muscle, but also within the

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brain.

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Now, what does this have to do with depression? Well,

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we reach that conclusion initially

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by doing some thinking

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looking at existing data which

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indicate that across many

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many studies. It was shown that

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exercise physical exercise.

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Has an antidepressant effect and I

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just mentioned the connection between exercise and

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lactate production.

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Also, there is evidence from other studies that

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there is

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a decrease in the density of this glial

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cells in the brain which are the

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cells that produce lactate.

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In depression in the brains of people deceased

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of many reasons,

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but who were had major depression?

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And also there were other evidences in the

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lab showing that until

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the some antidepressants would

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increase the levels of lactate produced

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by glial cells. So putting all this

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together we decided with my colleagues with

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collaborators in Geneva, Ronald

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Martin and Anthony carrar to

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test whether

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Very simply increasing lactate in the blood artificially

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by injecting it.

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Intraparitoneally would have

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an antidepressant effect in

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what are called animal models

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of depression and the main one

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is quite similar to what is the

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main risk factor for depression in humans

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and that's chronic stress or you

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can mimic chronic stress by injections of

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the ends the molec the

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stress hormone cortisol in

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humans and corticosterone in rodents. So

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giving chronically small doses

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of corticosterones to rodents makes

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them essentially depressed.

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So how do you

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quote unquote? How do you measure depression in or

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a depressed mood in rodents in

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rats or mice? Well, for example,

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they develop what is called

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an hedonia.

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Is lack of pleasure. So if you

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provide two bottles of water to

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rats or

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mice one containing Sweet Water the other

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plain water your normal rodent will

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drink essentially only Sweetwater.

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The depressed water unquote mouse or

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red will have no preference like a human

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really doesn't have any pleasure. So that's just

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one example.

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And in these animal models

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of depression we showed that lactate.

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Has an antidepressant effect because again these

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mice start again to drink sweet water or in

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other tests. They show no signs

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of depressed mood.

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So that's how we connected lactate exercise

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depression. And at the

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center of this are these known neuronal

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cells called glial cells or astrocytes in

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this case that produce lactate

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in the brain lactate is

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produced from from glucose

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series of reactions. And the last

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one is the conversion of lactate. Sorry

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of pyruvate into lactate.

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And that it needs what

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is called a cofactor kind of molecule that

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makes the reaction possible. And

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this is this

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reaction. This cofactor is

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is a molecule that can exist in two states NAD

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or nadh

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And ADH is the reduced form and nades you

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oxidized form. So whenever pyruvate is

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transformed to lactate.

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NAD is produced.

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Because lactate is more

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acidic than pyruvitz. So it takes one proton one

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hydrogen, but whenever like in

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neurons lack that is transformed back to

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pyruvate then it produces nadh.

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And so we reasoned that actually the

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the formation of nadh in neurons

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would be important.

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And for the effect the antidepressant effect

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of lactate because if rather than

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injected lactate into this quote-unquote depressed

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mice we injected pyruvate we had no

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effect.

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So the only difference between lactate and pyruvate is

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actually that lactate to

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pyruvate produces. Nadh as we

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know now from since maybe 20 years or

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so, maybe even more the brain

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actually continues to produce new neurons.

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And this process is called neurogenesis now

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for a long time use still maybe

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you maybe you know, maybe you don't but for a long

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time, but thought that that brains doesn't produce

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any neurons unlike skin

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or any other organ will produce new

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cells and actually the idea was even

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that the brain loses neurons with age and which

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is quite depressing but the good

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news came as I said 20 or so years ago showing

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that certain areas of the brain continue to

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produce.

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Um neurons throughout life in neurogenesis.

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That's a

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process.

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and it has been shown that stress

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again chronic stress, which is the

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main risk factor for depression inhibits neurogenesis

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and that classical antidepressants actually

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need neurogenesis to

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exert their

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antidepressant effect

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And so we wanted to check if this was also the case

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for lactate another new antidepressant.

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And and they need we showed that if we

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inhibit neurogenesis the effect of the antidepressant

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effect of lactate does not

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occur.

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There is a need for neurogenesis for the fa so

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that as now the the mechanisms we still

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working with my collaborators in

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Geneva on the molecular mechanisms of this

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but this is a strong observation and

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it implies that again depression stress

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depression inhibits neurogenesis.

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And most antidepressants and lactate ever

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exertory effect

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through neurogenesis.

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