Interactions between focused synaptic inputs and diffuse neuromodulation in the spinal cord

Abstract

Spinal motoneurons (MNs) amplify synaptic inputs by producing strong dendritic persistent inward currents (PICs), which allow the MN to generate the firing rates and forces necessary for normal behaviors. However, PICs prolong MN depolarization after the initial excitation is removed, tend to "wind-up" with repeated activation and are regulated by a diffuse neuromodulatory system that affects all motor pools. We have shown that PICs are very sensitive to reciprocal inhibition from Ia afferents of antagonist muscles and as a result PIC amplification is related to limb configuration. Because reciprocal inhibition is tightly focused, shared only between strict anatomical antagonists, this system opposes the diffuse effects of the descending neuromodulation that facilitates PICs. Because inhibition appears necessary for PIC control, we hypothesize that Ia inhibition interacts with Ia excitation in a "push-pull" fashion, in which a baseline of simultaneous excitation and inhibition allows depolarization to occur via both excitation and disinhibition (and vice versa for hyperpolarization). Push-pull control appears to mitigate the undesirable affects associated with the PIC while still taking full advantage of PIC amplification.

Figure 1

The relative amount of neuromodulatory drive sets the potential amplitude of the PIC and hence the amount of synaptic amplification. With weak monoaminergic drive, the PIC amplitude is small; synaptic current decreases as the cell is depolarized. As monoaminergic drive increases to medium and then strong, a progressively larger PIC and greater amplification of synaptic currents results. Inward (depolarizing) currents are downward.

Figure 2

When the MN is held at a hyperpolarized level (top trace, −90 mV), a brief excitatory input results in a depolarizing synaptic current with a sharp onset and offset that lasts for the duration of the input. At a more depolarized level (bottom trace,−55mV), the same brief excitatory input results in an amplified depolarizing current that persists (tail current) after the excitation is removed. Both the amplification and prolongation can be attributed to the PIC. Baseline current removed.

Figure 3

Experimental setup: A six degree-of-freedom robotic arm was used for passively rotating the ankle, knee, and hip joints.

Figure 4

A voltage ramp applied to a tricep surae MN at ankle position midpoint 1 results in the presence of a PIC (arrow on current trace). When the same ramp is applied with the hindlimb in the extension position there is a reduction in PIC amplitude. This reduction is due to the interaction between reciprocal inhibition from antagonist muscles and the PIC. At the flexion position, PIC activation is shifted (hyperpolarized). Midpoint 2 conditions are identical to midpoint 1.

Figure 5

(A) Single cell recording. The overlapping current traces demonstrate the differences in PIC amplitude at the different ankle positions. (B) Same cell as in A, following leak subtraction, with the ankle in the flexion position, synaptic amplification is greatest. At midpoints 1 and 2, the PIC amplitude is fairly similar and decreased from the flexion position. At the extension position, the PIC amplitude and synaptic amplification is smallest. Current traces are leak-subtracted.

Figure 6

Effective synaptic current in the tricep surae MN was recorded as the ankle, knee, and hip were flexed and extended individually and then in concert. The darker, thicker trace was a result of movements performed at a depolarized voltage, so that the PIC was activated. The thinner trace was a result of movements performed at a hyperpolarized voltage, below the threshold for activation of the PIC. In both voltage conditions it is apparent that the individual ankle and whole limb movements produce the largest amplitude compared to rotations of the knee or hip. This illustrates the focused nature of the cells receptive field.

Figure 7

The neuromodulatory inputs from the brainstem are diffuse involving all segments and laminae of the spinal cord. The Ia reciprocal inhibitory system is focused and helps “sculpt”movements out of a background of excitation.

Figure 8

When tonic levels of excitation and inhibition are present maximum depolarization (and maximum firing frequencies) are achieved when disinhibition is coupled with excitation. Similarly, maximum hyperpolarization is achieved by the coupling of disfacilitation with inhibition. In our experiments, this is achieved by having either an intact Ia reciprocal inhibition systemor disrupting reciprocal inhibition by cutting the tendons to antagonist muscles.