neuropeptide release

[Bill_Powers1]

From Bill Powers (970620.0820 MDT)]

John Anderson (960719) --

Yes. The neuropeptides are released from the same neuron that >releases

the small-molecule transmitter, and serve to modulate the >response of the
postsynaptic neuron to the small-molecule. They can >also affect events
some distance from the release site. I don't >know much more about it than
that, but I've attached a couple of >Medline abstracts ...

Still doesn't quite answer my questions, which seem to be multiplying. I
guess the first question is whether the neuropeptides released from a given
neuron are always the same ones; one of the abstracts indicates they are
"co-released with the primary transmitter," which seems to say that the
neural signals simply release some neuropeptides along with the primary
transmitters.

Second: it's said that the neuropeptides "modulate" the effects of the
primary transmitters. This seems to imply that the neuropeptides coming out
of a neuron have an effect on the way the primary transmitters affect the
synaptic processes. But if the neuropeptides are emitted along with the
primary transmitters, and if they're always the same at a given neuron, why
doesn't all this just add up to a different definition of the
neurotransmitter?

Which brings up the third question: can the amount of neuropeptide emitted
because of a given train of impulses _vary_ relative to the amount of
primary transmitter released (in a single synapse)? This would imply a
separate cause of emission of neuropeptides -- something else would be
acting to vary the amount of neuropeptide released by a given neural signal.

And, following that, the final question: what causes the amount of
neuropeptides released to vary? If the amount of neuropeptide can change
relative to the amount of primary transmitter, there must be some signal, a
chemical signal independent of the neural signal, that is altering the
chemical response of the neural vesicles to the neural signal. This would
make me want to backtrack the chemical signal to see what is generating it,
and so on.

Somehow I get the feeling that I shouldn't even be asking these questions!
I don't know enough about biochemistry to ask them intelligently, and
anyway even if I knew the answers I still wouldn't understand the system of
which these details are a part.

RE: your request for a writeup of PCT for your new web page: I will
consider it. Any suggestions as to content would be helpful.

Best,

Bill P.
P.S.; I am replying publicly to your direct post, because there are some
others who are interested.

[John_E_Anderson1]

[From John Anderson (970622.2030 EDT)]

>From Bill Powers (970620.0820 MDT)]

John Anderson (960719) --

>Yes. The neuropeptides are released from the same neuron that >releases
the small-molecule transmitter, and serve to modulate the >response of the
postsynaptic neuron to the small-molecule. They can >also affect events
some distance from the release site. I don't >know much more about it than
that, but I've attached a couple of >Medline abstracts ...

Still doesn't quite answer my questions, which seem to be multiplying. I
guess the first question is whether the neuropeptides released from a given
neuron are always the same ones; one of the abstracts indicates they are
"co-released with the primary transmitter," which seems to say that the
neural signals simply release some neuropeptides along with the primary
transmitters.

It is my understanding that a given neuron can only release a certain
set of neuropeptides in addition to the primary transmitter. An example
(from Gordon Shepherd's _Neurobiology 3rd edition_ (1994), pp185-186)
would be neurons projecting to the ventral horn of the spinal cord which
can secrete the small molecule transmitter serotonin, and the
neuropeptides thyrotropin releasing hormone and substance P.

Second: it's said that the neuropeptides "modulate" the effects of the
primary transmitters. This seems to imply that the neuropeptides coming out
of a neuron have an effect on the way the primary transmitters affect the
synaptic processes. But if the neuropeptides are emitted along with the
primary transmitters, and if they're always the same at a given neuron, why
doesn't all this just add up to a different definition of the
neurotransmitter?

Because the answer to your next question is yes:

Which brings up the third question: can the amount of neuropeptide emitted
because of a given train of impulses _vary_ relative to the amount of
primary transmitter released (in a single synapse)? This would imply a
separate cause of emission of neuropeptides -- something else would be
acting to vary the amount of neuropeptide released by a given neural signal.

Well, now that I look closer, I see that what you are asking is whether
_identical_ trains of impulses can release different amounts of the
peptides. I don't think this happens, outside of statistical
fluctuations in vesicle release. But see the answer to your final
question.

And, following that, the final question: what causes the amount of
neuropeptides released to vary? If the amount of neuropeptide can change
relative to the amount of primary transmitter, there must be some signal, a
chemical signal independent of the neural signal, that is altering the
chemical response of the neural vesicles to the neural signal. This would
make me want to backtrack the chemical signal to see what is generating it,
and so on.

I don't think there is a chemical signal which varies the amount of
peptide relative to primary transmitter. But different input levels
will release varying amounts of peptide along with the primary
transmitter. The following is paraphrased from Shepherd's text
describing events occurring in the ventral horn synapse.

With low frequency action potential input, the synapse releases only
serotonin which depolarizes the postsynaptic cell. With a little higher
frequency of input, the serotonin binds to autoreceptors on the
presynaptic cell, inhibiting further serotonin release. But at a still
slightly higher frequency of impulses, there is co-release of the
peptide. There are several sites at which the peptide may act. It may
act on the presynaptic side, to block the autoreceptors for the
transmitter, freeing the terminal from feedback inhibition, and leading
to increased serotonin release and increased postsynaptic response.
Alternatively, it may act on the postsynaptic terminal, where it could
change the affinity of the serotonin receptor, or it could act on a
separate receptor that is linked to a second messenger system. A third
mode of operation might be for the peptide to have independent actions
on membrane or cytosolic receptors which in turn act on the nucleus
(this applies especially to steroid hormones), and there may also be
direct actions in the nucleus.

I am still looking for a more recent and accessible review of
neuropeptide co-release. I've found a more accessible but slightly
older review. It is:

Kupfermann I "Functional studies of cotransmission" Physiol Rev 71
(3):683-732

I'm going to try to get hold of a copy tomorrow or the next day.

RE: your request for a writeup of PCT for your new web page: I will
consider it. Any suggestions as to content would be helpful.

I received your draft for the IBTRC (thanks!), but I haven't had a
chance to read it yet. As soon as I do, I'll let you know.

John

···

--
John E. Anderson
jander@unf.edu

[Bill_Powers1]

[From Bill Powers (970622.1904 MDT)]

John Anderson (970622.2030 EDT)--

Thanks for all the patient answers Re neuropeptide generation. Your last
answer approaches what I was most curious about -- the variation in
neuropeptide output relative to the primary neurotransmitter as a function
of input signal frequency.

For purposes of understanding gross brain function, I think about the
lowest level of detail that would be helpful is the level of neural
input-output functions: frequency in, frequency out. When you get below
that level, the amount of information you need to derive the neural
function gets to be enormous: you have to understand every input as well as
all the internal chemistry. The problem is that at the chemical level, the
observations are too spotty to give us a picture of what is going on: vis,

···

==================
With low frequency action potential input, the synapse releases only
serotonin which depolarizes the postsynaptic cell. With a little higher
frequency of input, the serotonin binds to autoreceptors on the presynaptic
cell, inhibiting further serotonin release. But at a still lightly higher
frequency of impulses, there is co-release of the peptide.

This tells us what happens with the chemistry, but it doesn't say what the
consequences are in terms of the firing of the receiving neuron as the
presynaptic input frequency rises and falls. You can't see the forest for
the trees.

I think that in general it's better to start at a more global level and
find out what a system does, and then look at the details to see how it
does it. In the case of a neuron, we want to characterize the output
firings as a function of all the input firings that affect the cell. Just
consider the common case where an incoming axon arborizes as it reaches the
dendrites of the receiving cell. In each synapse, it might be true that at
low input frequencies you get seretonin transmission only, which tends to
saturate at somewhat higher frequencies, and then a co-release of a
neuropeptide at still higher frequencies. But over all the synapses
involved in the multiple connections from the incoming axon, these effects
might occur at slightly different input frequencies, so the overall input
effect might simply be a continuous linear increase in net excitation as
the input frequency increases. The shift from seretonin to seretonin +
peptide might simply be a mechanism for extending the dynamic range of the
input signal. From the standpoint of what the neural connection _does_,
it's the overall transformation of the input signal into an output signal
that matters.

Thus step of characterizing the overall function is an essential one
in figuring out how brain chemistry affects brain function. It's a step
that tends to be left out -- many people like to jump directly from
neurotransmitter chemistry to behavioral characteristics of the whole
person, a practice I deplore.

Best,

Bill P.

[John_E_Anderson1]

[From John Anderson (970623.0030)]

Bill Powers (970622.1904 MDT)--

I think that in general it's better to start at a more global level and
find out what a system does, and then look at the details to see how it
does it...

This step of characterizing the overall function is an essential one
in figuring out how brain chemistry affects brain function. It's a step
that tends to be left out -- many people like to jump directly from
neurotransmitter chemistry to behavioral characteristics of the whole
person, a practice I deplore.

I think this is where PCT has the most to offer biological brain
science, in providing a functional framework within which to view the
details that most experimental findings in neuroscience consist of. But
the biological basis of the control hierarchy needs to be strengthened,
to better relate the various levels to neuroanatomy. Then we can see
how the details fit in.

John

···

--
John E. Anderson
jander@unf.edu

[Bill_Powers1]

[From Bill Powers (970623.0608 MDT)]

John Anderson (970623.0030)--

I think this is where PCT has the most to offer biological brain
science, in providing a functional framework within which to view >the

details that most experimental findings in neuroscience consist >of. But
the biological basis of the control hierarchy needs to be >strengthened, to
better relate the various levels to neuroanatomy. >Then we can see how the
details fit in.

Agreed. I think that some information is available, and that the levels in
the PCT hierarchy do - roughly -- correspond to levels of function that
have been found in the brain, at least as I knew them in a cursory way 25
years ago. I've always hoped that someone with a real talent for grasping
masses of neurological data (not me!) would take on the job of sorting out
levels, not just anatomically but experimentally -- remember that my
definitions of levels have never had the benefit of hundreds of minds
working to refine and modify them. My feeble attempts to draw a hierarchy
of control are only a crude sketch on the back of an envelope.

Neuroanatomy can take one only so far. The difference between a neural
multiplier and a neural adder is a matter of parameter values, not
connections, and of course it makes all the difference in what part a
neural connection plays in the overall system function. Also, neuroanatomy
is far from standardized across individuals -- the same system-level
function can be accomplished in any number of ways, and there's no reason
to think that different people have the same detailed neuroanatomy. The
"hard wired" concept of brain connections, I think, has long been disproven.

That means that the link between brain chemistry and behavior is even more
tenuous. When people try to link ubiquitous substances like seretonin or
dopamine to systemic problems like schizophrenia, this makes me think of an
electronics engineer studying the effects of boron on the bandwidth of a
radio receiver. There is, of course, a connection, in that a batch of
integrated citcuits with the wrong level of boron doping will not work very
well in the receiver, but the reason is not any specific chemical effect on
circuit performance. If you have a bad design, correcting the level of
boron doping will not fix it. There are a couple -- at least -- of missing
steps between boron doping and circuit function. As there are between brain
chemistry -- or genes -- and behavior.

Best,

Bill P.

[John_E_Anderson1]

[From John Anderson (970623.0030 EDT)]

Bill Powers (970623.0608 MDT) --

Also, neuroanatomy
is far from standardized across individuals -- the same system-level
function can be accomplished in any number of ways, and there's no reason
to think that different people have the same detailed neuroanatomy. The
"hard wired" concept of brain connections, I think, has long been disproven.

Different people certainly don't have the same _detailed_ neuroanatomy;
if we did, we'd all be the same. But the overall layout of the system
is the same from person to person. We all have a thalamus that relays
sensory information to the cortex, our visual cortex is in the back of
our brain, and so on. It's in these common characteristics that we
should look first for the components of the control hierarchy, something
that you started in B:CP.

John

···

--
John E. Anderson
jander@unf.edu

[Bill_Powers1]

[From Bill Powers (970624.0857 MDT)]

John Anderson (970623.0030 EDT) --

Different people certainly don't have the same _detailed_ >neuroanatomy;

if we did, we'd all be the same.

Not so. Neuronatomy describes only what neurons are connected to what other
neurons. But the _function_ of such connections is determined by the
relationship of input frequencies to output frequencies, and that depends
on the pre- and post-synaptic chemistry, which determines the parameters of
the transformation. You can't tell how a neuron is transforming the input
signals just from looking at the pathways. Different people, identically
connected, could behave entirely differently. But of course they're not
identically connected -- far from it.

But the overall layout of the system is the same from person to >person.

We all have a thalamus that relays sensory information to >the cortex, our
visual cortex is in the back of our brain, and so >on. It's in these
common characteristics that we should look first >for the components of the
control hierarchy, something that you >started in B:CP.

Yes, I agree, but this is only a hint as to what is going on -- a hint
about organization. It doesn't tell us what _functions_ are performed in
each of these anatomically-described volumes of the brain. It was these
global aspects of organization that led me to think of levels of perception
and control, but I'm still not sure of what those levels are in terms of
what they DO.

Best,

Bill P.