Hans Hultborn

Immobilization leads to multiple simultaneous adaptive changes in muscle, connective tissue, and central nervous system.

Editorial: Neuromodulatory Control of Spinal Function in Health and Disease

Significance: Behaviors are realized through concerted activity in neural circuits. This activity results from a combination of neural connectivity and the properties of the involved neurons. By studying the activity of neurons in the human subthalamic nucleus during surgery for Parkinson’s disease, we report that these neurons have multiple stable states, and that brief electrical stimuli can lead to transitions between states. We thus suggest that these neurons function as finite state machines. The different states could influence the function of key motor circuits of the basal ganglia, and thus knowledge of these states in disease or in response to treatment could help to define new treatment strategies for people with movement disorders.

The output from a motor nucleus is determined by the synaptic input to the motor neurons and their intrinsic properties. Here, we explore whether the source of synaptic inputs to the motor neurons (cats) and the age or post-stroke conditions (humans) may change the recruitment gain of the motor neuron pool. In cats, the size of Ia EPSPs in triceps surae motor neurons (input) and monosynaptic reflexes (MSRs; output) was recorded in the soleus and medial gastrocnemius motor nerves following graded stimulation of dorsal roots. The MSR was plotted against the EPSP thereby obtaining a measure of the recruitment gain. Conditioning stimulation of sural and peroneal cutaneous afferents caused significant increase in the recruitment gain of the medial gastrocnemius, but not the soleus motor neuron pool. In humans, the discharge probability of individual soleus motor units (input) and soleus H-reflexes (output) was performed. With graded stimulation of the tibial nerve, the gain of the motor neuron pool was assessed as the slope of the relation between probability of firing and the reflex size. The gain in young subjects was higher than in elderly subjects. The gain in post-stroke survivors was higher than in age-matched neurologically intact subjects. These findings provide experimental evidence that recruitment gain of a motor neuron pool contributes to the regulation of movement at the final output stage from the spinal cord and should be considered when interpreting changes in reflex excitability in relation to movement or injuries of the nervous system.

In the motor system, force gradation is achieved by recruitment of motoneurons and rate modulation of their firing frequency. Classical experiments investigating the relationship between injected current to the soma during intracellular recording and the firing frequency (theI–frelation) in cat spinal motoneurons identified two clear ranges: a primary range and a secondary range. Recent work in mice, however, has identified an additional range proposed to be exclusive to rodents, the subprimary range (SPR), due to the presence of mixed mode oscillations of the membrane potential. Surprisingly, fully summated tetanic contractions occurred in mice during SPR frequencies. With the mouse now one of the most popular models to investigate motor control, it is crucial that such discrepancies between observations in mice and basic principles that have been widely accepted in larger animals are resolved. To do this, we have reinvestigated theI–frelation using ramp current injections in spinal motoneurons in both barbiturate-anesthetized and decerebrate (nonanesthetized) cats and mice. We demonstrate the presence of the SPR and mixed mode oscillations in both species and show that the SPR is enhanced by barbiturate anesthetics. Our measurements of theI–frelation in both cats and mice support the classical opinion that firing frequencies in the higher end of the primary range are necessary to obtain a full summation. By systematically varying the leg oil pool temperature (from 37°C to room temperature), we found that only at lower temperatures can maximal summation occur at SPR frequencies due to prolongation of individual muscle twitches.SIGNIFICANCE STATEMENTThis work investigates recent revelations that mouse motoneurons behave in a fundamentally different way from motoneurons of larger animals with respect to the importance of rate modulation of motoneuron firing for force gradation. The current study systematically addresses the proposed discrepancies between mice and larger species (cats) and demonstrates that mouse motoneurons, in fact, use rate modulation as a mechanism of force modulation in a similar manner to the classical descriptions in larger animals.

Aromatic L-amino acid decarboxylase (AADC) is an essential enzyme in the synthesis of serotonin, dopamine, and certain trace amines and is present in a variety of organs including the brain and spinal cord. It is previously reported that in mammalian spinal cord AADC cells (called D-cells) were largely confined to a region around the central canal and that they do not produce monoamines. To date, there has not been a detailed description of their distribution and morphology in mammals. In the present study this issue is systematically investigated using immunohistochemistry. We have found that AADC cells in the rat spinal cord are both more numerous and more widely distributed than previously reported. In the gray matter, AADC neurons immunolabeled for NeuN were not only found in the region around the central canal but also in the dorsal horn, intermediate zone, and ventral horn. In the white matter a large number of glial cells were AADC-immunopositive in different spinal segments and the vast majority of these cells expressed oligodendrocyte and radial glial phenotypes. Additionally, a small number of AADC neurons labeled for NeuN were found in the white matter along the ventral median fissure. The shapes and sizes of AADC neurons varied according to their location. For example, throughout cervical and lumbar segments AADC neurons in the intermediate zone and ventral horn tended to be rather large and weakly immunolabeled, whereas those in comparable regions of sacrocaudal segments were smaller and more densely immunolabeled. The diverse morphological characteristics of the AADC cells suggests that they could be further divided into several subtypes. These results indicate that AADC cells are heterogeneously distributed in the rat spinal cord and they may exert different functions in different physiological and pathological situations.

Botulinum toxin (Btx) is used in children with cerebral palsy and in other neurological patients to diminish spasticity and reduce the risk of development of contractures. We investigated changes in the central gain of the stretch reflex circuitry in response to Btx injection in the triceps surae muscle in rats. Experiments were performed in 21 rats. Eight rats were a control group, and 13 rats were injected with 6 IU of Btx in the left triceps surae muscle. Two weeks after Btx injection, larger monosynaptic reflexes (MSR) were recorded from the left (injected) than the right (noninjected) L4 + L5 ventral roots following stimulation of the corresponding dorsal roots. A similar increase on the left side was observed in response to stimulation of descending motor tracts, suggesting that increased excitability of spinal motor neurons may at least partly explain the increased reflexes. However, significant changes were also observed in postactivation depression of the MSR, suggesting that plastic changes in transmission from Ia afferent to the motor neurons also may be involved. The data demonstrate that muscle paralysis induced by Btx injection is accompanied by plastic adaptations in the central stretch reflex circuitry, which counteract the antispastic effect of Btx.NEW & NOTEWORTHY Injection of botulinum toxin into ankle muscles causes increased gain of stretch reflex. This is caused by adaptive changes in regulation of transmitter release from Ia afferents and increased excitability of spinal motor neurons.

Aromatic L-amino acid decarboxylase (AADC) cells are widely distributed in the spinal cord and their functions are largely unknown. We have previously found that AADC cells in the spinal cord could increase their ability to produce serotonin from 5-hydroxytryptophan after spinal cord injury (SCI). Since AADC is a common enzyme catalyzing 5-hydroxytryptophan to serotonin and L-dopa to dopamine (DA), it seems likely that the ability of AADC cells using L-dopa to synthesize DA is also increased. To prove whether this is the case a same rat sacral SCI model and a similar experimental paradigm were adopted as we used previously (Wienecke et al., J. Neurosci. 34, 11984, 2014). In the chronic SCI rats (> 45d), no AADC cells expressed DA if there was no exogenous L-dopa application. However, following administration of a peripheral AADC inhibitor (carbidopa) with or without a monoamine oxidase inhibitor (pargyline) co-application, systemic administration of L-dopa resulted in ~ 94% of AADC cells to become DA-immunopositive in the spinal cord below the lesion, whereas in normal or sham-operated rats none or very few of AADC cells became DA-immunopositive with the same treatment. Using tail electromyography, spontaneous tail muscle activity was increased nearly 5-fold over the baseline level. When pretreated with a central AADC inhibitor (NSD1015), further application of L-dopa failed to increase the motoneuron activity although the expression of DA in the AADC cells was not completely inhibited. These findings demonstrate that AADC cells in the spinal cord below the lesion gain the ability to produce DA from its precursor in response to SCI. This ability also enables the AADC cells to produce 5-HT and trace-amines, and likely contributes to the development of hyperexcitability. These results might also be implicated for revealing the pathological mechanisms underlying L-dopa-induced dyskinesia in Parkinson’s disease.