Neuromodulation of motoneuronal processing of dynamic synaptic inputs

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.