Summary/Abstract
All motor commands flow through motoneurons (MNs), which are probably the most thoroughly studied of all
spinal neurons. Perhaps the most striking result to emerge from the many studies of MNs is that
neuromodulatory input from the brainstem exerts an enormous impact on motoneuron excitability, via
monosynaptic synapses releasing either serotonin (5HT) or norepinephrine (NE). However, the primary focus
of studies of this fundamental transformation has been on slowly varying synaptic inputs. Consequently,
neuromodulatory actions on inputs with fast temporal dynamics remain poorly understood. This uncertainty at
the foundation of motor output is a major limitation. Rapid movements are obviously essential for normal motor
behavior. Furthermore, transient inputs, such as H-reflexes and transcranial magnetic stimuli, are fundamental
for understanding circuitry of sensorimotor systems in humans and other animals in both normal and
pathological states. Our overall goal is to determine how integration of dynamic synaptic inputs in MNs is
impacted by brainstem neuromodulatory input. The previous focus on slow/steady inputs likely occurred
because a primary target for the brainstem neuromodulatory systems is a persistent inward current (PIC) that
activates very slowly and, once fully active, is highly resistant to inactivation. Thus neuromodulatory facilitation
of PICs generates input amplification up to 5-fold and input prolongation up to 10 seconds or more, depending
on the level of 5HT or NE released by brainstem axons. The PIC however has two main components, one
mediated by Ca channels (CaPIC) and the other by Na channels (Na PIC). The CaPIC provides the slow, non-
inactivating behavior whereas the NaPIC is much faster activating and much less resistant to inactivation. 5HT
and NE also lower motoneuron recruitment thresholds (via actions on the spike voltage threshold) and greatly
alter the driving forces for excitatory and inhibitory postsynaptic potentials (because the CaPIC strongly
depolarizes the dendrites). Together, the NaPIC, threshold reduction and driving force alteration mean that
dynamic inputs may be nearly as sensitive to neuromodulation as slow inputs. We will investigate these
neuromodulatory effects on MNs across the full range of temporal dynamics of input, from transient to steady.
We will deploy array electrode recordings on muscles to assess population firing patterns in Aim 1, in situ
voltage clamp techniques to elucidate cellular mechanisms in Aim 2. The transformation of cellular to
population behaviors will be investigated by realistic MN models implemented on a supercomputer in Aim 3.
Large differences in integration of slow versus fast inputs are likely to be fundamental for understanding normal
behavior and for interpretation of the strength of synaptic connections based on transient stimulation in
humans (H reflexes, TMS, etc) in both normal behaviors and neurological diseases and injuries.