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The Antidepressant Effects of Lactate

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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

00:06.600 --> 00:09.700
Lactate is a product of

00:09.700 --> 00:12.300
glucose metabolism glucose is the fuel

00:12.300 --> 00:15.500
for any cell older cells in in the body

00:15.500 --> 00:16.500
including.

00:18.500 --> 00:22.100
some of the cells in the brain and so

00:21.100 --> 00:24.500
glucose is

00:24.500 --> 00:25.100
transformed to

00:26.100 --> 00:30.500
a pyruvate and then pyruvate can enter what we

00:30.500 --> 00:33.500
call oxidation and produce energy

00:33.500 --> 00:36.400
or some of the pyruvate is transformed

00:36.400 --> 00:39.300
to lactate and for a long time. It was thought that

00:39.300 --> 00:40.700
lactating type was a

00:41.400 --> 00:44.700
An interesting metabolic and product the real molecule

00:44.700 --> 00:47.600
being pyruvate that then can be burned and

00:47.600 --> 00:48.300
produce energy.

00:49.100 --> 00:53.100
Well, it turns out that lactate is not at

00:52.100 --> 00:55.500
all an end product because it's actually

00:55.500 --> 00:57.200
exported from cells.

00:58.800 --> 01:01.700
Taken up by other cells converted back

01:01.700 --> 01:05.700
to pyruvate and then in produces energy

01:04.700 --> 01:07.300
in other cells. So

01:07.300 --> 01:10.700
that's why there are in the body what are

01:10.700 --> 01:13.200
called lactate shuttles because like it is

01:13.200 --> 01:17.700
formed in certain cells exported and used

01:16.700 --> 01:19.500
by other cells. That's a

01:19.500 --> 01:23.000
general principle that is emerging in Biochemistry.

01:23.700 --> 01:26.600
And my work over the years showed

01:26.600 --> 01:30.100
that in the brain this dialogue occurs between

01:29.100 --> 01:32.800
two cell types lack that

01:32.800 --> 01:35.200
is produced by glial cells. These are

01:35.200 --> 01:38.300
no neuronal cells that make up half of

01:38.300 --> 01:41.600
the brain. These are the cells that mainly take

01:41.600 --> 01:43.000
up glucose from the blood.

01:43.700 --> 01:46.400
Converted to lactate and then release it

01:46.400 --> 01:49.500
for neurons which use it and

01:49.500 --> 01:52.900
this is called the astrocyte neuron lactate shuttle.

01:53.700 --> 01:57.300
Now, what does this have to do with the exercise

01:56.300 --> 01:59.600
and depression? Well during exercise

01:59.600 --> 02:03.400
muscles produce lactate

02:02.400 --> 02:06.400
because there is also a shuttle

02:05.400 --> 02:08.200
there a lactate shuttle that was

02:08.200 --> 02:11.300
actually initially described by a colleague George

02:11.300 --> 02:14.400
Brooks at UC Berkeley

02:14.400 --> 02:17.300
and he showed that

02:17.300 --> 02:21.000
certain cells in muscles produce lactate

02:20.100 --> 02:24.400
and other cells other muscle cells

02:24.400 --> 02:27.300
use lactate. So that's there's a shuttle there

02:27.300 --> 02:27.600
again.

02:28.600 --> 02:31.800
And during exercise there is lactate

02:31.800 --> 02:36.600
that is produced and shuttled

02:34.600 --> 02:37.900
between the two

02:37.900 --> 02:41.200
metabolic cells

02:40.200 --> 02:43.600
the two muscle cells, but then

02:43.600 --> 02:47.500
there is also lactic that goes into the bloodstream some

02:46.500 --> 02:50.200
is taken up by the liver.

02:49.200 --> 02:53.100
And actually the pathway

02:52.100 --> 02:55.200
goes backwards. So from lack that

02:55.200 --> 02:59.100
you go back to glucose. It's called gluconeogenesis, but

02:58.100 --> 03:02.000
also some liked it is remains

03:01.200 --> 03:04.900
in the circulation and it's taken up by the

03:04.900 --> 03:07.500
brain and there it can be used

03:07.500 --> 03:08.200
by neurons.

03:09.200 --> 03:12.500
Also whenever we move so we

03:12.500 --> 03:15.600
exercise we we activate brain regions

03:15.600 --> 03:19.300
whereby glucose enters

03:18.300 --> 03:21.500
into the brain in those more active

03:21.500 --> 03:24.800
regions is transformed to lactate by

03:24.800 --> 03:27.300
this glial cells is astrocytes and

03:27.300 --> 03:30.600
then lactate is used by by neurons.

03:30.600 --> 03:33.500
So in a nutshell lactate is

03:33.500 --> 03:36.700
definitely not a metabolic and product. It's

03:36.700 --> 03:40.300
actually a very precious metabolic product

03:39.300 --> 03:43.800
that provides a shackling

03:42.800 --> 03:45.100
of energy between cells

03:46.300 --> 03:50.800
And it is produced during exercise in

03:49.800 --> 03:52.200
muscle, but also within the

03:52.200 --> 03:52.500
brain.

03:53.500 --> 03:57.900
Now, what does this have to do with depression? Well,

03:56.900 --> 04:01.600
we reach that conclusion initially

04:00.600 --> 04:04.200
by doing some thinking

04:03.200 --> 04:06.900
looking at existing data which

04:06.900 --> 04:09.600
indicate that across many

04:09.600 --> 04:12.300
many studies. It was shown that

04:12.300 --> 04:13.900
exercise physical exercise.

04:14.900 --> 04:17.800
Has an antidepressant effect and I

04:17.800 --> 04:20.600
just mentioned the connection between exercise and

04:20.600 --> 04:21.400
lactate production.

04:22.100 --> 04:26.200
Also, there is evidence from other studies that

04:25.200 --> 04:28.300
there is

04:28.300 --> 04:31.800
a decrease in the density of this glial

04:31.800 --> 04:34.600
cells in the brain which are the

04:34.600 --> 04:35.900
cells that produce lactate.

04:36.500 --> 04:41.200
In depression in the brains of people deceased

04:39.200 --> 04:43.800
of many reasons,

04:43.800 --> 04:46.300
but who were had major depression?

04:47.400 --> 04:51.500
And also there were other evidences in the

04:50.500 --> 04:54.800
lab showing that until

04:53.800 --> 04:56.600
the some antidepressants would

04:56.600 --> 04:59.600
increase the levels of lactate produced

04:59.600 --> 05:02.400
by glial cells. So putting all this

05:02.400 --> 05:06.000
together we decided with my colleagues with

05:05.200 --> 05:09.600
collaborators in Geneva, Ronald

05:08.600 --> 05:12.100
Martin and Anthony carrar to

05:11.100 --> 05:13.500
test whether

05:14.200 --> 05:18.100
Very simply increasing lactate in the blood artificially

05:17.100 --> 05:19.100
by injecting it.

05:19.900 --> 05:22.500
Intraparitoneally would have

05:22.500 --> 05:25.500
an antidepressant effect in

05:25.500 --> 05:28.900
what are called animal models

05:28.900 --> 05:31.500
of depression and the main one

05:31.500 --> 05:35.000
is quite similar to what is the

05:34.100 --> 05:37.200
main risk factor for depression in humans

05:37.200 --> 05:41.100
and that's chronic stress or you

05:40.100 --> 05:43.900
can mimic chronic stress by injections of

05:43.900 --> 05:47.000
the ends the molec the

05:46.400 --> 05:50.700
stress hormone cortisol in

05:50.700 --> 05:55.100
humans and corticosterone in rodents. So

05:54.100 --> 05:57.700
giving chronically small doses

05:57.700 --> 06:02.100
of corticosterones to rodents makes

06:00.100 --> 06:05.600
them essentially depressed.

06:03.600 --> 06:06.000
So how do you

06:06.300 --> 06:10.500
quote unquote? How do you measure depression in or

06:09.500 --> 06:12.800
a depressed mood in rodents in

06:12.800 --> 06:15.400
rats or mice? Well, for example,

06:15.400 --> 06:18.200
they develop what is called

06:18.200 --> 06:19.600
an hedonia.

06:19.800 --> 06:22.300
Is lack of pleasure. So if you

06:22.300 --> 06:25.600
provide two bottles of water to

06:25.600 --> 06:28.000
rats or

06:28.200 --> 06:31.200
mice one containing Sweet Water the other

06:31.200 --> 06:34.600
plain water your normal rodent will

06:34.600 --> 06:37.300
drink essentially only Sweetwater.

06:38.300 --> 06:42.000
The depressed water unquote mouse or

06:41.100 --> 06:44.500
red will have no preference like a human

06:44.500 --> 06:47.600
really doesn't have any pleasure. So that's just

06:47.600 --> 06:48.200
one example.

06:49.100 --> 06:52.900
And in these animal models

06:52.900 --> 06:55.800
of depression we showed that lactate.

06:56.600 --> 06:59.600
Has an antidepressant effect because again these

06:59.600 --> 07:02.700
mice start again to drink sweet water or in

07:02.700 --> 07:05.700
other tests. They show no signs

07:05.700 --> 07:07.200
of depressed mood.

07:08.200 --> 07:12.400
So that's how we connected lactate exercise

07:11.400 --> 07:14.500
depression. And at the

07:14.500 --> 07:17.600
center of this are these known neuronal

07:17.600 --> 07:21.100
cells called glial cells or astrocytes in

07:20.100 --> 07:24.300
this case that produce lactate

07:23.300 --> 07:26.600
in the brain lactate is

07:26.600 --> 07:30.900
produced from from glucose

07:30.900 --> 07:33.700
series of reactions. And the last

07:33.700 --> 07:36.800
one is the conversion of lactate. Sorry

07:36.800 --> 07:38.900
of pyruvate into lactate.

07:39.600 --> 07:42.400
And that it needs what

07:42.400 --> 07:45.500
is called a cofactor kind of molecule that

07:45.500 --> 07:48.900
makes the reaction possible. And

07:48.900 --> 07:51.600
this is this

07:51.600 --> 07:54.300
reaction. This cofactor is

07:54.300 --> 07:58.200
is a molecule that can exist in two states NAD

07:57.200 --> 07:59.600
or nadh

08:00.300 --> 08:04.100
And ADH is the reduced form and nades you

08:03.100 --> 08:06.500
oxidized form. So whenever pyruvate is

08:06.500 --> 08:07.700
transformed to lactate.

08:08.300 --> 08:09.700
NAD is produced.

08:10.800 --> 08:13.000
Because lactate is more

08:13.800 --> 08:17.000
acidic than pyruvitz. So it takes one proton one

08:16.500 --> 08:19.800
hydrogen, but whenever like in

08:19.800 --> 08:22.200
neurons lack that is transformed back to

08:22.200 --> 08:25.600
pyruvate then it produces nadh.

08:26.200 --> 08:29.700
And so we reasoned that actually the

08:29.700 --> 08:34.300
the formation of nadh in neurons

08:32.300 --> 08:35.500
would be important.

08:36.300 --> 08:39.400
And for the effect the antidepressant effect

08:39.400 --> 08:42.400
of lactate because if rather than

08:42.400 --> 08:45.800
injected lactate into this quote-unquote depressed

08:45.800 --> 08:48.300
mice we injected pyruvate we had no

08:48.300 --> 08:48.600
effect.

08:49.400 --> 08:52.600
So the only difference between lactate and pyruvate is

08:52.600 --> 08:55.300
actually that lactate to

08:55.300 --> 08:58.600
pyruvate produces. Nadh as we

08:58.600 --> 09:01.500
know now from since maybe 20 years or

09:01.500 --> 09:05.200
so, maybe even more the brain

09:04.200 --> 09:07.900
actually continues to produce new neurons.

09:08.800 --> 09:11.500
And this process is called neurogenesis now

09:11.500 --> 09:14.300
for a long time use still maybe

09:14.300 --> 09:17.000
you maybe you know, maybe you don't but for a long

09:17.200 --> 09:20.600
time, but thought that that brains doesn't produce

09:20.600 --> 09:23.500
any neurons unlike skin

09:23.500 --> 09:26.400
or any other organ will produce new

09:26.400 --> 09:29.300
cells and actually the idea was even

09:29.300 --> 09:33.100
that the brain loses neurons with age and which

09:32.100 --> 09:35.600
is quite depressing but the good

09:35.600 --> 09:38.600
news came as I said 20 or so years ago showing

09:38.600 --> 09:41.200
that certain areas of the brain continue to

09:41.200 --> 09:41.600
produce.

09:43.200 --> 09:47.700
Um neurons throughout life in neurogenesis.

09:46.700 --> 09:49.300
That's a

09:49.300 --> 09:49.500
process.

09:50.300 --> 09:54.100
and it has been shown that stress

09:53.100 --> 09:56.200
again chronic stress, which is the

09:57.100 --> 10:02.200
main risk factor for depression inhibits neurogenesis

10:02.800 --> 10:06.600
and that classical antidepressants actually

10:06.600 --> 10:09.700
need neurogenesis to

10:09.700 --> 10:11.000
exert their

10:12.100 --> 10:13.600
antidepressant effect

10:14.300 --> 10:17.400
And so we wanted to check if this was also the case

10:17.400 --> 10:20.800
for lactate another new antidepressant.

10:21.500 --> 10:24.300
And and they need we showed that if we

10:24.300 --> 10:28.000
inhibit neurogenesis the effect of the antidepressant

10:27.300 --> 10:30.200
effect of lactate does not

10:30.200 --> 10:30.600
occur.

10:31.300 --> 10:34.300
There is a need for neurogenesis for the fa so

10:34.300 --> 10:37.600
that as now the the mechanisms we still

10:37.600 --> 10:40.200
working with my collaborators in

10:40.200 --> 10:43.300
Geneva on the molecular mechanisms of this

10:43.300 --> 10:47.100
but this is a strong observation and

10:46.100 --> 10:50.400
it implies that again depression stress

10:49.400 --> 10:53.100
depression inhibits neurogenesis.

10:53.600 --> 10:58.400
And most antidepressants and lactate ever

10:56.400 --> 11:00.300
exertory effect

11:00.300 --> 11:01.700
through neurogenesis.

00:06 - Lactate is a product of glucose metabolism glucose is the fuel for any cell older cells in in the body including. some of the cells in the brain and so glucose is

00:24 - transformed to a pyruvate and then pyruvate can enter what we call oxidation and produce energy or some of the pyruvate is transformed to lactate and for a long time. It was thought that lactating type was a An interesting metabolic and product the real molecule being pyruvate that then can be burned and produce energy. Well, it turns out that lactate is not at

00:52 - all an end product because it's actually exported from cells. Taken up by other cells converted back to pyruvate and then in produces energy in other cells. So that's why there are in the body what are called lactate shuttles because like it is formed in certain cells exported and used by other cells. That's a general principle that is emerging in Biochemistry.

01:23 - And my work over the years showed that in the brain this dialogue occurs between two cell types lack that is produced by glial cells. These are no neuronal cells that make up half of the brain. These are the cells that mainly take up glucose from the blood. Converted to lactate and then release it for neurons which use it and this is called the astrocyte neuron lactate shuttle.

01:53 - Now, what does this have to do with the exercise and depression? Well during exercise muscles produce lactate because there is also a shuttle there a lactate shuttle that was actually initially described by a colleague George Brooks at UC Berkeley and he showed that certain cells in muscles produce lactate and other cells other muscle cells

02:24 - use lactate. So that's there's a shuttle there again. And during exercise there is lactate that is produced and shuttled between the two metabolic cells the two muscle cells, but then there is also lactic that goes into the bloodstream some is taken up by the liver. And actually the pathway

02:52 - goes backwards. So from lack that you go back to glucose. It's called gluconeogenesis, but also some liked it is remains in the circulation and it's taken up by the brain and there it can be used by neurons. Also whenever we move so we exercise we we activate brain regions whereby glucose enters into the brain in those more active

03:21 - regions is transformed to lactate by this glial cells is astrocytes and then lactate is used by by neurons. So in a nutshell lactate is definitely not a metabolic and product. It's actually a very precious metabolic product that provides a shackling of energy between cells And it is produced during exercise in muscle, but also within the

03:52 - brain. Now, what does this have to do with depression? Well, we reach that conclusion initially by doing some thinking looking at existing data which indicate that across many many studies. It was shown that exercise physical exercise. Has an antidepressant effect and I just mentioned the connection between exercise and

04:20 - lactate production. Also, there is evidence from other studies that there is a decrease in the density of this glial cells in the brain which are the cells that produce lactate. In depression in the brains of people deceased of many reasons, but who were had major depression? And also there were other evidences in the

04:50 - lab showing that until the some antidepressants would increase the levels of lactate produced by glial cells. So putting all this together we decided with my colleagues with collaborators in Geneva, Ronald Martin and Anthony carrar to test whether Very simply increasing lactate in the blood artificially by injecting it.

05:19 - Intraparitoneally would have an antidepressant effect in what are called animal models of depression and the main one is quite similar to what is the main risk factor for depression in humans and that's chronic stress or you can mimic chronic stress by injections of the ends the molec the stress hormone cortisol in

05:50 - humans and corticosterone in rodents. So giving chronically small doses of corticosterones to rodents makes them essentially depressed. So how do you quote unquote? How do you measure depression in or a depressed mood in rodents in rats or mice? Well, for example, they develop what is called an hedonia.

06:19 - Is lack of pleasure. So if you provide two bottles of water to rats or mice one containing Sweet Water the other plain water your normal rodent will drink essentially only Sweetwater. The depressed water unquote mouse or red will have no preference like a human really doesn't have any pleasure. So that's just one example.

06:49 - And in these animal models of depression we showed that lactate. Has an antidepressant effect because again these mice start again to drink sweet water or in other tests. They show no signs of depressed mood. So that's how we connected lactate exercise depression. And at the center of this are these known neuronal cells called glial cells or astrocytes in

07:20 - this case that produce lactate in the brain lactate is produced from from glucose series of reactions. And the last one is the conversion of lactate. Sorry of pyruvate into lactate. And that it needs what is called a cofactor kind of molecule that makes the reaction possible. And this is this

07:51 - reaction. This cofactor is is a molecule that can exist in two states NAD or nadh And ADH is the reduced form and nades you oxidized form. So whenever pyruvate is transformed to lactate. NAD is produced. Because lactate is more acidic than pyruvitz. So it takes one proton one hydrogen, but whenever like in

08:19 - neurons lack that is transformed back to pyruvate then it produces nadh. And so we reasoned that actually the the formation of nadh in neurons would be important. And for the effect the antidepressant effect of lactate because if rather than injected lactate into this quote-unquote depressed mice we injected pyruvate we had no effect.

08:49 - So the only difference between lactate and pyruvate is actually that lactate to pyruvate produces. Nadh as we know now from since maybe 20 years or so, maybe even more the brain actually continues to produce new neurons. And this process is called neurogenesis now for a long time use still maybe you maybe you know, maybe you don't but for a long time, but thought that that brains doesn't produce

09:20 - any neurons unlike skin or any other organ will produce new cells and actually the idea was even that the brain loses neurons with age and which is quite depressing but the good news came as I said 20 or so years ago showing that certain areas of the brain continue to produce. neurons throughout life in neurogenesis. That's a

09:49 - process. and it has been shown that stress again chronic stress, which is the main risk factor for depression inhibits neurogenesis and that classical antidepressants actually need neurogenesis to exert their antidepressant effect And so we wanted to check if this was also the case for lactate another new antidepressant.

10:21 - And and they need we showed that if we inhibit neurogenesis the effect of the antidepressant effect of lactate does not occur. There is a need for neurogenesis for the fa so that as now the the mechanisms we still working with my collaborators in Geneva on the molecular mechanisms of this but this is a strong observation and it implies that again depression stress

10:49 - depression inhibits neurogenesis. And most antidepressants and lactate ever exertory effect through neurogenesis.

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