Memory, Pain,
Depression, and Peptides... Putting the Pieces Together
By Jason Socrates
Bardi
Sometimes the greatest moments in one's professional career
are those in which one's accomplishments are not recognized.
Such a moment occurred for Tamas Bartfai in 1983, when he
wrote a paper together with Tomas Hokfelt and Jan Lundberg
claiming that he had identified a neuron that used not just
one, but two neurotransmitters. They had discovered, in these
neurons, the coexistence of the acetylcholine (ACH) and vasoactive
intestinal polypeptide (VIP), two molecules that are released
into synapses and transmit nerve impulses—a coexistence
that was not thought possible at the time.
His manuscript was less than well received.
"We were rejected from every major journal," says Bartfai,
who is professor of neuropharmacology and director of the
Harold L. Dorris Neurological Research Center at The Scripps
Research Institute (TSRI). "'It is well known that a neuron
can have only one transmitter or we would have cacophony in
the brain,' wrote one Nobel laurate referee."
Today there are over 40 well-documented examples of neurons
with coexisting neutotransmitters. These examples have been
described in thousands of papers, and more are discovered
every year.
"I am quite pleased when I look at that paper rejected by
Nature," he says.
What's in a Brain
Bartfai describes himself as a molecular neurobiologist—someone
who attempts to associate cellular and molecular mechanisms
to the phenomenon of cognition. Bartfai's own interests involve
specifically identifying the molecular correlates of changes
in long-term memory and in emotional states.
These attempts are, by Bartfai's own admission, mere starting
points. Cognition is a complicated subject from a molecular
perspective due to the number of neurons, neurotransmitters,
and interconnections. There are emotional components, attentional
components, sensory inputs, the creation and retention of
short- and long-term memory, and the molecular interactions
between these disparate events. There are stimuli and signals
to be sorted out, and different regions of the brain that
are involved in the different types of memory.
"We think in terms of very few transmitters and very few
neurons and very few connectivities when we imagine how all
of this works as compared to the trillions of nerve cells
that actually participate," says Bartfai. "Where are these
proteins formed, and are they specific to memory or to a circuit?
What are the rules for reading them out when you recall a
memory?"
"These are things that we don't really know much about,"
he says.
Understanding the connection between cellular and molecular
interactions and cognition is one of Bartfai's key goals,
but he also wants to find ways of turning these basic observations
into useful therapeutics—therapeutics to counter degenerative
diseases like Alzheimer's disease, which is characterized
by a loss of memory.
Long-term memory involves the synthesis of new proteins,
a characteristic that makes it amenable to someone like Bartfai,
who is a biochemist by training. Because new proteins are
formed as memories are formed, proteins and memories could,
in theory, be alternatively blocked by synthesis inhibitors
or enhanced by regulating the production of those inhibitors.
But, says Bartfai, at the moment, we are only really good
at identifying non-specific ways of impairing memory, such
as through alcohol. There are no drugs proven to enhance human
cognitive ability or to help bring damaged cognition back
to a more normal state.
"To stop the decline of memory," says Bartfai. "That is
what we are really talking about—not making super IQ's,
because there are enough of those already."
Unveiling the Effects of Peptides
One of the systems on which Bartfai is working is neurons
that, like those he identified in 1983, use two distinct neurotransmitters.
These are the cholinergic neurons that project to the hippocampus,
and he is actively pursuing them because they are concentrated
in a locus—called the Nucleus Basalis—which
provides acetylcholine input to the hippocampus, is important
for cognition, and which is severely damaged in Alzheimer's
disease.
The hippocampus is a ridge of tissue along the lateral ventrals
of the brain sandwiched between the cerebral cortex and the
thalamus. This is where we think many of the chemical processes
take place that are important for forming and retaining memories,
the basic processes of cognition.
Cholinergic inputs to the hippocampus contain both the neurotransmitter
acetylcholine (ACh) and the neuropeptide galanin.
These two chemicals coexist specifically in those hippocampus
neurons, and both chemicals are released into the gaps, or
synapses, between two neurons during the signaling from one
neuron to another that takes place during cognitive processes.
Acetylcholine is a well characterized neurotransmitter and
one with which Bartfai is very familiar. In the early 1970s,
simultaneous with S.H. Snyder and Sir Arnold Burgen, he made
the first identification of muscarinic ACh receptors in the
brain, which are one type of neuronal receptors for acetylcholine,
and his research in this area has continued since then.
"In the end," says Bartfai, "everything we do in my laboratory
turns out to have to do with modifying the cholinergic activity
in the brain."
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