Those who have heard me talk about the brain know that I have a complete paradigm for the role of the fundamental neuromodulators, one I developed about a decade ago. A minimally thorough version of that theory filled a 62-page term paper for Personality Psychology, and a short version of the argument for just one of the six chemicals (acetylcholine) was a 39-page paper for another course. Nevertheless, I’ve explained it all in fifty minutes on several different occasions … so let’s see if there’s a 1000-word blog post version.
Five of the six neuromodulators constitute a system I call the “control brain” (the sixth, adenosine, is probably the most important of them all and is way outside the scope of this summary). The control brain doesn’t do any thinking or feeling; its job is to control the rest of the brain (the “main brain”) so that our style of thinking and feeling can be varied to match our circumstances. You can think of each and every neuron in the main brain as having a “volume knob” and a “tone control” which determine the degree and style of their activity, respectively. The control brain is a system for globally turning these knobs, in a coordinated fashion.
Physically, the control brain is located in the brainstem, just above the mechanisms that control the body. Here there are “factories” for the five chemicals (this is a good time to point out that a summary this brief is full of oversimplifications; for instance, one of the five chemicals is actually made in the hypothalamus, which is just above the brainstem, and another has a second factory even higher up in the brain). All of the brain’s serotonin, for instance, is made in a tiny cluster of cells in the brainstem called the raphe nuclei. The neurons of a chemical factory do not project to their neighbors, like the majority of neurons in the brain. Instead, their axons (business ends, where the chemical is released) project up into the main brain, branching and subdividing endlessly, so that each serotonin-releasing neuron synapses on (“innervates”) thousands of target neurons. Serotonin is the signal that turns the volume knob on these cells, and the relative handful of serotonin-producing cells in the raphe nuclei are thus able to control the entire brain.
What’s initially puzzling is that there are five parallel control systems. But the actual situation is even more complex, because (as already implied) the five chemicals target two different parameters in the target neurons (the "volume" and "tone" controls"). We’ve already mentioned dopamine (DA) and its hypothesized roles in holding information in active memory, and in turning on aspects of phenomenal consciousness (subjective experience), such feelings of desire. DA is the sole chemical that turns up only the tone control (the ubiquitous chemical cAMP), which tells us that it's part of a system for priming information for conscious access and actually placing it into consciousness. That half of the chemical paradigm, like the role of adensone, is outside the scope of this summary, but the short version is that DA primes information in active memory, serotonin (5-HT) primes information in long-term memory, and norepinephrine (NE) adds its cAMP boost to push information over the threshold of consciousness. 5-HT thus essentially handles the past, NE the present, and DA the future.
Four of the chemicals turn up the "volume control," a chemical called PLC that triggers a cascade that boosts intracellular calcium level and hence makes cells more likely to fire (whereas cAMP ultimately alters the shape and hence behavior of proteins, such as receptors). That leaves the second half of the chemical paradigm with four parameters to discover, and that’s a good number. You could, for instance, explain four parameters with a 2 x 2 design, for instance, two different ways of controlling two different things.
Let’s start by observing that the brain stores information, and that the chief feature of the storage system is that information is connected to other information (that song reminds me of you). So there are two fundamental types of neural circuitry in the brain’s storage system: circuitry which encodes information, and circuitry which connects information to other information. You would want to control these two types of circuits independently. Adjusting the volume (PLC activity, calcium level) on the encoding circuits would have the effect of controlling the level of general brain activity, which is probably the most obvious parameter of them all. Adjusting the volume on the connecting circuits would control the degree of associative spread, the degree to which things remind you of other things. And that is a very good thing to control; there are times you want to be empirical or characterizing and think just about the facts, and times you want to be interpretive and thing about all the implications of the facts. (The savvy among you may have realized that I have just described the Jungian “sensing / intuition” dichotomy which constitutes one of the traits of the MBTI.)
So all we need to complete the paradigm is two different ways of controlling these two types of circuits. And we have that already: it was in the last part, where we hypothesized a multiplicative signal to increase the salience gradient. A multiplicative signal is of course contrasted with a simple additive signal. An additive signal “pays no attention” to the level of activity in its target; a plus 5 additive signal turns 0 to 5, 5 to 10, and 10 to 15. A multiplicative signal does “pay attention to” the level of activity in its target, by getting feedback from it; a times 5 multiplicative signal leaves 0 as 0, but turns 5 to 25 and 10 to 50.
So, one chemical controls the encoding circuits additively, and another controls them multiplicatively. And another pair of chemicals controls the connecting circuits, again, one additively and one multiplicatively.
Histamine is known to be the brain’s chief mediator of cortical arousal, the primary determinant of whether you’re asleep or awake (this is why antihistamines cause drowsiness), and is thus the obvious candidate for the chemical that additively controls the encoding circuits. Acetylcholine (ACh) additively controls the connecting circuits and hence associative spread (the brain defaults to maximum associativeness and ACh inhibits the spread); this hypothesis explains a wealth of observations, from the nature of cognition during REM sleep (when ACh levels are higher than in waking) to the cognitive style of those at risk for Alzheimer’s (a disease which targets ACh neurons exclusively).
That leaves us with two chemicals: norepinephrine (NE) and serotonin (5-HT), which are made right next to each other and have profoundly similar patterns of innervation (the other three are unique). And they must be the two multiplicative signals.
The idea that serotonin is a multiplicative inhibiting signal for the brain’s connecting circuits turns out to have huge explanatory power. By being multiplicative, it has no affect on the ordinary weak connections like “that song reminds me of you.” But it is the only way that strong connections, like deeply felt beliefs and lifelong emotional responses, can be broken and hence rearranged. I’ve been proposing that serotonin fundamentally controls cognitive and emotional flexibility for well over a decade, and the world is slowly coming around to share that idea. But I’m fairly certain I’m the only person who can explain how serotonin does this at a low level of neural circuitry.
And that leaves us with norepinephrine as the multiplicative signal for information encoding, and hence the chemical that controls the salience gradient. In the next post, we’ll explore how much sense this makes.