Sir John Eccles, 1903-1997: Part 2: The Brain as a Machine or as a Site of Free Will?

The Purkinje Dendrites

When compared with the great Purkinje
Other cell's dendrites look so stingy
That we must be highly critical
Of models not enough dentritical.

It won't suffice to note with unction
The size of a climbing fibre junction.
We surely must stress the intermingling
Of its message with the parallel ting-a-lingling
Which duly serves to give preference
To only the smoothest of all efferents

So that we may duly work our will
Whether running, jumping or standing still.

--Michael Arbib (1968; quoted in Eccles 1973b)

This sequel to the paper on Sir John Eccles which appeared in the previous issue of Perspectives (Karczmar 2001) describes Eccles' explorations in the 1960s of integrative interplay between the neurotransmitters at nerve cells. This interplay, together with the particular design of the neuronal circuitry of the cerebellum, hippocampus, and cortex, renders the brain capable of functioning like a well-regulated machine. Paradoxically, at the time he was carrying out these studies, Eccles expanded his exploration of the uniquely human consciousness and free will.¹

Inhibitions and Interactions

The first step in this research was to dismantle the rigid image of central transmission presented by David Lloyd (1941), who posited that "inhibitory and excitatory actions on the motoneurones" have identical central latencies, and hence "that inhibition of motoneurones is exerted through a monosynaptic central path via a 'direct inhibition'" (Eccles 1961, 1964). Precise measurement of time relations of discharges in the inhibitory circuitry of the Renshaw cell and elsewhere, and the pharmacological analysis of the Renshaw cell events, allowed Eccles to demonstrate that inhibitions result from disynaptic rather than monosynaptic events; specifically, he and his associates showed that inhibitions represent recurrent rather than direct disynaptic inhibitory pathways that involve, via interneurons and the mediation of excitatory and inhibitory neurotransmitters, conversion of excitation into inhibition. This circuitry represents an example of negative postsynaptic feedback that begins, at the interneuron, with the depolarizing excitatory potential (epsp) or current and terminates with hyperpolarizing postsynaptic potential (ipsp) or current. These phenomena imparted the character of functional flexibility to the central transmission not provided by Lloyd's conceptualization. Subsequently, Eccles' research added another dimension to this concept, as he demonstrated the presence of interneuronally mediated postsynaptic feed-forward inhibition in the case of the spinal control of antagonistic musculature as well as in higher centers including the cerebellum, hippocampus, and thalamus (Andersen and Eccles 1962).

Another source of integration and regulation of central transmission is provided by presynaptic inhibition. This story starts with the dorsospinal electric field and its P potential wave which are evoked by dorsal root volleys and which were associated by Gasser and Graham (1933) with the inhibition of the flexor response. Eccles, et al. (1961), and Frank and Fuortes (1967) proved that the P wave reflects depolarization of the presynaptic afferent terminals; this presynaptic depolarization decreases the release of the pertinent transmitter and hence depresses the postsynaptic (inhibitory or excitatory) potential (Eccles et al. 1961). Presynaptic inhibition is evoked far from the dendrites of the recipient (effector) neuron; thus, it is called "remote inhibition." Subsequently, Eccles and his associates demonstrated presynaptic inhibition in the thalamus, cerebellum, hippocampus, and the cuneate nucleus of the medulla (Eccles 1964). Pre- and post-synaptic inhibitions differ pharmacologically, as the former are blocked (partially) by picrotoxin and the latter by strychnine (Andersen et al. 1963). This difference implies that the presynaptic inhibition is mediated by a different transmitter than the postsynaptic inhibitor, glycine; this transmitter has subsequently been shown to be GABA. Today, besides glycine and GABA, other transmitters, such as peptides and acetylcholine, are known to be involved in inhibitions.

The final mode of flexibility and integration is afforded by the interactions of the pre- and post-synaptic potentials. Eccles...