8. Molecular formal inversion - C.

Bacteria. In bacterial brain-mind homologues there are formal inversions in cell-to-cell systems rather like the virus-to-cell inversions in the previous post. One example is the fimbriae mechanism. The fimbriae are very fine hair-like protein filaments that grow out from the surface of a bacterium and enable it to adhere to other cells. The presence or absence of fimbriae on E. coli is determined by inversion of the promoter region of the gene called fim A, as shown.

There is another kind of bacterial formal inversion switch that works on larger protein outgrowths called flagella. For example, as in the sketch shown in post 4, a flagellum (or motor unit) of E. coli works by rotating clockwise or anticlockwise. When the bacterium detects an attractant chemical, the molecular brain-mind homologue of the cell signals the 5 to 10 flagella to rotate anticlockwise and collect into a sort of pony-tail that drives the cell in a 'run' towards the chemical. When a repellent chemical is detected, the flagella rotate clockwise and fly apart so that the cell is said to 'tumble' at an angle to the run and away from the chemical. The run and tumble effect is yet another example of the formal inversion principle being deployed in the interests of survival.

9. Formal inversion in a Radiata model.

We have been edging our way from molecular stimulus-response systems and brain-mind homologues towards the emergence of their neural counterparts, which first appeared in the Radiata. A standard laboratory model for these typically jar-shaped, blind-gutted, radially symmetric animals is the freshwater Hydra. The hydra polyp is attached by its base (B) and has an upward pointing mouth/anus (MA) surrounded by a zone of tentacles (T).

The nervous system of a hydra is a body-wide nerve net (NN) via which any stimulus anywhere provokes a full body response. The key structure for our purpose is the nerve ring, which is a thick neuron bundle running round the circumference of the animal between the mouth/anus and the tentacles. Its key developmental feature is its stability. Whereas the rest of the hydra nervous system undergoes constant cell replenishment, the nerve ring does not. The nerve ring is thus a highly credible candidate for a simple brain.

The Radiata represent the most likely evolutionary stage at which the circularity factor became an integral part of our own brain heritage (some 1300 million years ago according to modern 'molecular clocks'). There are at least six arguable theories as to how Radiata nervous systems became Bilateria nervous systems (like those of humans) and one of these is simplistically shown. The main point for the present argument is that at this stage, before the advent of bilaterality and forward foraging, all brains were unicyclic.

When the nerve ring is examined closely, as schematised in the lower diagrams, it is seen to be made of chains of individual neurons in which signals from any stimulus travel in both (mutually inverted) directions round the ring.

10. Formal inversion in C. elegans - A.

We have now arrived at the famous Minimal Bilateria Model of animal life called C. elegans (in the upper diagram). This tiny (1 mm long) creature is the most completely understood multicellular animal in science. It was the first to have its genome sequenced and thus provided central lessons for the human genome project.

It also has the only nervous system in a multicellular animal for which we have an essentially complete wiring diagram, including that of a Minimal Model Brain, represented by the contents of the box in the diagram. Here the black dots represent neuron cell bodies and the nerve ring is the probable homologue of the nerve ring of the hydra. This magnificent neuroscientific resource (the wiring diagram) was provided in 1986, after seventeen years of intricate electron microscopy and painstaking reconstruction, by the Cambridge team of John White, Eileen Southgate, Nichol Thomson and Sydney Brenner *. [The upper diagram and several diagrams in following posts were developed from data published in their now classic report].

The brain of C. elegans is capable of such fundamental activities as taste, smell, touch sensation and heat sensation, all of which are also central to our own lives. The mind (or working brain) of 'the worm', as it is known to its devotees, is also capable of learning, memory and thus primitive knowledge. Crucially for science however, the worm brain/mind achieves all these functions with about 180 neurons and about 4000 interconnections -- an entirely tractable conceptual challenge compared with the enormous complexity of human brains. We are thus able to begin to learn about the basic workings of brains while it is still possible to study them neuron by neuron and connection by connection.

In the next post we shall begin to look 'inside the box' at the brain of the worm.

* White J. G., Southgate E., Thomson J. N., Brenner S. (1986). The structure of the nervous system of the nematode Caenorhabditis elegans. Phil. Trans. R. Soc. London. B314, 1-340. [Also accessible on the Web at www.wormbase.org Click on The Mind of a Worm (White et al. 1986).

11. Formal inversion in C. elegans - B.

A Minimal Model Bilateria Brain. Each black blob here represents the cell body of a neuron. The nerve ring of cell fibres and its extension into the belly of the worm is shown in yellow. The main brain circuitry for our current 'broad brush' purposes is the amphid complex, which includes circuits for taste, smell, touch and heat sensation -- all of which have evolved equivalents in our own brains and some of which are already known to be involved in learning and memory in the worm.

You should now imagine that you are looking at the worm brain from above and behind as indicated by the yellow arrow -- and that you can see four neurons, as in the next picture.

[Diagram developed from data published by White et al. (1986)].

12. Formal inversion in C. elegans - C.

Diagram developed from data published by White et al. (1986).

The four neurons have been artificially separated. To envisage the natural state, imagine the nearly circular parts superimposed on one another. These nearly circular parts contribute to the nerve ring -- the 'highest' structure in the worm brain and the homologue of our own cerebral cortex. Expressed simplistically, the homologous structures are the sites where the respective animals (representing minimal and maximal Bilateria) do the most sophisticated 'thinking' of which they are capable.

The black dots connected by coloured lines are sample connections between neurons.

• Green(ish) lines represent connections on the same side of the animal,
• Red(ish) lines between the two sides and different neuron pairs, and
• Blue lines between two sides and within a neuron pair.

[the 'ish' of the green and red lines refers to the fact that the scanning method has lost some of the colour of the original artwork. I shall hope to improve these colours in due course.]

In evolutionary terms, the green connections will eventually become the critically important association fibres and the red and blue connections the critically important commissural fibres in our own brains -- so that the scientific value of the minimal model brain in beginning to understand our own thinking processes can hardly be overstated.

Two other important points about this stage of Minimal Bilateria neural evolution should be appreciated. First, neurons were already manifest as three broad types: cells to receive stimuli (sensory neurons), cells to trigger responses (motor neurons) and cells to connect the two (interneurons) -- the basic arrangement that continues in all subsequent Bilateria including humans. In later animals, the three neuron types were to become increasingly structurally complex but whereas the sensory and motor neurons also increased their number in each circuit to a relatively small degree, the interneuron parts of circuits were to expand hugely to produce more and more powerful brains.

Second, connections between neurons were already of the two main types that occur in all later animals (chemical and electrical) but such connections were made via relatively simple 'touching points' between adjacent neuron processes -- a situation best imagined by the superimposition mentioned above. Such en passant connections were the earliest kind of neuron linkage in bilateral animals. In later animals such direct links were generally replaced by much more complex devices.

Because the worm brain has only about 180 neurons and only around 4000 such connections, it is possible to work out various basic circuits, as in the example in the next post.

13. Formal inversion in C. elegans - D.

A CIRCUIT FOR A 'MINIMAL MODEL THOUGHT' CONCERNING TASTE

[Diagram developed from data published by White et al. (1986).]

The circuit illustrates some of the fundamental workings of the worm homologue of our human cerebral cortex. As an informal description of the circuit's activity, the worm in the diagram may be envisaged as having a 'minimal model thought' concerning taste.

Two main sensory cells for taste (at the top of the figure) are called ASE. The left is ASEL and the right ASER. When the worm detects certain chemicals in the outside world, signals flow in the direction of the arrows.

The sensory neurons connect with interneurons called AIB (left and right again). Note that at this stage the signals change direction. The previously clockwise left signals now travel anticlockwise, and the inverse is the case on the other side. Note also that in making the connections at this level, the ASEL-AIBR connections are one-way and that the ASER-AIBL connections are two-way or circular. The latter pattern is emphasised in the upper right dotted yellow box.

How have these patterns been revealed? By use of a newly developed technique called a connectogram, which will be illustrated in the next picture.

14. Formal inversion in C. elegans - E.

Connectogram for amphid

SENSORY NEURONS and INTERNEURONS

All the sensory neurons are listed in rows and all the interneurons in columns. Each dot represents a chemical connection site identified by White et al. (1986) on a sensory neuron and each small square surrounding a dot represents a corresponding connection site similarly identified on an interneuron.

The small diagram on the left shows the plotting key: TO the left and TO the right in upper quadrants and FROM the left and FROM the right in lower quadrants.

If you now look at the two yellow squares, where the taste circuitry begins, you will see that the two (red) connections from the left sensory neuron to the right interneuron are one-way and that the opposite connection (from the right sensory neuron to the left interneuron) is two-way or circular.

Note that such circular left/right connection patterns (red sites, one above the other and within the same grid square) occur in four places in key circuits.

Two of these are concerned with the main taste circuit initiated by the ASE neurons: the above-mentioned yellow square (ASER-AIBL) example and another at ASER-AIAL.

Another is concerned with the main smell circuit initiated by the AWC neurons: namely at AWCR-AIYL.

The other is concerned with the main thermosensation circuit initiated by the AFD neurons: at AFDL-AINR.

Newcomers to C. elegans data will by now have begun to appreciate the value of the Minimal Model Brain (and its Minimal Model 'Thoughts') at this very early stage in our quest to understand the many mysteries of our own brains and minds. In the next post we shall return to the main demonstration taste circuit.