α-Motoneurons maintain biophysical heterogeneity in obesity and diabetes in Zucker rats

Small-diameter sensory dysfunction resulting from diabetes has received much attention in the literature, whereas the impact of diabetes on α-motoneurons (MN) has not. In addition, the chance of developing insulin resistance and diabetes is increased in obesity. No study has examined the impact of obesity or diabetes on the biophysical properties of MN. Lean Zucker rats and Zucker diabetic fatty (ZDF) rats were separated into lean, obese (ZDF fed standard chow), and diabetic (ZDF fed high-fat diet that led to diabetes) groups. Glass micropipettes recorded hindlimb MN properties from identified flexor and extensor MN. MN were separated within their groups on the basis of input conductance, which created high- and low-input conductance subpopulations for each. A significant shorter (20%) afterhyperpolarization half-decay (AHP1/2) was found in low-conductance MN for the diabetic group only, whereas AHP½ tended to be shorter in the obese group (19%). Significant positive correlations were found among rheobase and input conductance for both lean and obese animals. No differences were found between the groups for afterhyperpolarization amplitude (AHPamp), input conductance, rheobase, or any of the rhythmic firing properties (frequency-current slope and spike-frequency adaptation index). MN properties continue to be heterogeneous in obese and diabetic animals. Obesity does not seem to influence lumbar MN. Despite the resistance of MN to the impact of diabetes, the reduced AHP1/2 decay and the tendency for a reduction in AHPamp may be the first sign of change to MN function. NEW & NOTEWORTHY Knowledge about the impact of obesity and diabetes on the biophysical properties of motoneurons is lacking. We found that diabetes reduces the duration of the afterhyperpolarization and that motoneuron function is unchanged by obesity. A reduced afterhyperpolarization may impact discharge characteristics and may be the first sign of change to motoneuron function.

The dynamics of somatic input processing in spinal motoneurons in vivo

Uncovering how motoneurons utilize their voltage-sensitive conductances to systematically respond to a variety of inputs is paramount to understanding synaptic integration. In this study, we examine the input dynamics and frequency-dependent characteristics of active conductances in motoneurons as viewed from the soma in the decerebrate cat. We evaluated the somatic response of the motoneuron by superimposing a voltage sinus sweep (a sine wave in which frequency increases with time, which is often referred to as a zap or chirp) at a subset of membrane holding potentials during discontinuous, single-electrode, somatic voltage-clamp. Results from both experimental and modeling data indicate that ionic conductances can respond to a wide variety of input dynamics. Notably, it appears that there is a divergence between low input conductance type S and high input conductance type FF motoneurons in their response to input frequency. Type S motoneurons generate a larger response to lower frequency input dynamics (compared with their response to higher frequencies), whereas type FF generate a larger response to higher input frequency dynamics. Functionally, these results may indicate that motoneurons on the lower end of the motor pool (i.e., recruited first) may favor steady inputs, whereas motoneurons at the higher end (i.e., recruited later) may favor input transients in producing action potentials.

Characteristics and Organization of Discharge Properties in Rat Hindlimb Motoneurons

The discharge properties of hindlimb motoneurons in ketamine–xylazine anesthetized rats were measured to assess contributions of persistent intrinsic currents to these characteristics and to determine their distribution in motoneuron pools. Most motoneurons (30/37) responded to ramp current injections with adapting patterns of discharge and the frequency–current ( f– I) relations of nearly all motoneurons included a steep subprimary range of discharge. Despite the prevalence of adapting f– I relations, responses included indications that persistent inward currents (PICs) were activated, including increased membrane noise and prepotentials before discharge, as well as counterclockwise hysteresis and secondary ranges in f– I relations. Examination of spike thresholds and afterhyperpolarization (AHP) trajectories during repetitive discharge revealed systematic changes in threshold and trajectory within the subprimary, primary, and secondary f– I ranges. These changes in the primary and secondary ranges were qualitatively similar to those described previously for cat motoneurons. Within the subprimary range, AHP trajectories often included shallow approaches to threshold following recruitment and slope of the AHP ramp consistently increased until the subprimary range was reached. We suggest that PICs activated near recruitment contributed to these slope changes and formation of the subprimary range. Discharge characteristics were strongly correlated with motoneuron size, using input conductance as an indicator of size. Discharge adaptation, recruitment current, and frequency increased with input conductance, whereas both subprimary and primary f– I gains decreased. These results are discussed with respect to potential mechanisms and their functional implications.

Persistent Currents and Discharge Patterns in Rat Hindlimb Motoneurons

We report here the first direct measurements of persistent inward currents (PICs) in rat hindlimb motoneurons, obtained from ketamine–xylazine anesthetized rats during slow voltage ramps performed by single-electrode somatic voltage clamp. Most motoneurons expressed PICs and current–voltage ( I– V) relations often contained a negative-slope region (NSR; 13/19 cells). PICs activated at −52.7 ± 3.89 mV, 9 mV negative to spike threshold. NSR onset was −44.2 ± 4.1 mV. PIC amplitudes were assessed by maximum inward currents measured relative to extrapolated leak current and to NSR-onset current. PIC conductance at potentials just positive to activation was assessed by the relative change in slope conductance ( gin/ gleak). PIC amplitudes varied widely; some exceeded 5 and 10 nA relative to current at NSR onset or leak current, respectively. PIC amplitudes did not vary significantly with input conductance, but PIC amplitudes normalized by recruitment current decreased with increasing input conductance. Similarly, gin/ gleak decreased with increasing input conductance. Currents near resting potential on descending limbs of I– V relations were often outward, relative to ascending-limb currents. This residual outward current was correlated with increases in leak conductance on the descending limb and with input conductance. Excluding responses with accommodation, residual outward currents matched differences between recruitment and derecruitment currents, suggesting a role for residual outward current in frequency adaptation. Comparison of potentials for PIC activation and NSR onset with interspike trajectories during discharge demonstrated correspondence between PIC activation and frequency–current ( f– I) range boundaries. Contributions of persistent inward and outward currents to motoneuron discharge characteristics are discussed.

Role for the Subthreshold Currents ILeak and IH in the Homeostatic Control of Excitability in Neocortical Somatostatin-Positive Inhibitory Neurons

Cortical circuitry reconfigures in response to chronic (1–3 days) changes in activity levels. To understand this process, we must know the role played by inhibitory neurons because they crucially influence network properties by controlling action potential generation and synaptic integration. Using pharmacological blockade of activity in neocortical organotypic slice cultures, we examined the activity-dependent regulation of membrane excitability in a specific inhibitory neuron subtype: the somatostatin-positive (SOM+) neuron. Chronic action potential blockade (TTX, 2.5 days) resulted in increased excitability in SOM+ neurons. This result is consistent with a homeostatic process to maintain the average firing rate of SOM+ neurons at a particular level. Excitability changes were not ascribed to changing cell size or alterations in voltage-dependent sodium current. Instead, the excitability increase was largely the result of a decrease in the density of two subthreshold currents: a passive leak current ( ILeak) and H-current ( IH). The downregulation of these currents increased excitability mostly through a decrease in membrane input conductance. The coadaptation of ILeak and IH enabled a change in input conductance while helping to preserve membrane potential. Evidence indicated that ILeak was probably mainly mediated by K+. At earlier culture ages, this adaptation was superimposed on developmental changes, whereas at older ages, the same types of induced alterations occurred but with no developmental component. Together with other studies, these data indicate that both inhibitory and excitatory neurons increase membrane excitability with chronic reduction in activity, but through different mechanisms.

How Membrane Properties Shape the Discharge of Motoneurons: A Detailed Analytical Study

Electrophysiological experiments and modeling studies have shown that after hyperpolarization regulates the discharge of lumbar motoneurons in anesthetized cats and is an important determinant of their firing properties. However, it is still unclear how firing properties depend on slow after hyperpolarization, input conductance, and the fast currents responsible for spike generation. We study a single-compartment integrate-andfire model with a slow potassium conductance that exponentially decays between spikes. We show that this model is analytically solvable, and we investigate how passive and active membrane properties control the discharge. We show that the model exhibits three distinct firing ranges (primary, secondary, and high frequency), and we explain the origin of these three ranges. Explicit expressions are established for the gain of the steady-state current-frequency (I− f) curve in the primary range and for the gain of the I− f curve for the first interspike interval. They show how the gain is controlled by the maximal conductance and the kinetic parameters of the after hyperpolarization conductance. The gain also depends on the spike voltage threshold, and we compute how it is decreased by threshold accommodation (i.e., the increase of the threshold with the injected current). In contrast, the gain is not very sensitive to the input conductance. This implies that tonic synaptic activity shifts the current-frequency curve in its primary range, in agreement with experiments. Taking into account the absolute refractory period associated with spikes somewhat reduces the gain in the primary range. More importantly, it accounts for the approximately linear and steep secondary range observed in many motoneurons. In the nonphysiological high-frequency range, the behavior of the I− f curve is determined by the fast voltage-dependent currents, via the amplitude of the fast repolarization afterspike, the duration of the refractory period, and voltage threshold accommodation, if present.

Influence of Active Dendritic Currents on Input-Output Processing in Spinal Motoneurons In Vivo

The extensive dendritic tree of the adult spinal motoneuron generates a powerful persistent inward current (PIC). We investigated how this dendritic PIC influenced conversion of synaptic input to rhythmic firing. A linearly increasing, predominantly excitatory synaptic input was generated in triceps ankle extensor motoneurons by slow stretch (duration: 2–10 s) of the Achilles tendon in the decerebrate cat preparation. The firing pattern evoked by stretch was measured by injecting a steady current to depolarize the cell to threshold for firing. The effective synaptic current ( I N, the net synaptic current reaching the soma of the cell) evoked by stretch was measured during voltage clamp. Hyperpolarized holding potentials were used to minimize the activation of the dendritic PIC and thus estimate stretch-evoked I N for a passive dendritic tree ( I N,PASS). Depolarized holding potentials that approximated the average membrane potential during rhythmic firing allowed strong activation of the dendritic PIC and thus resulted in marked enhancement of the total stretch-evoked I N( I N,TOT). The net effect of the dendritic PIC on the generation of rhythmic firing was assessed by plotting stretch-evoked firing (strong PIC activation) versus stretch-evoked I N,PASS (minimal PIC activation). The gain of this input-output function for the neuron (I-ON) was found to be ∼2.7 times as high as for the standard injected frequency current ( F-I) function in low-input conductance neurons. However, about halfway through the stretch, firing rate tended to become constant, resulting in a sharp saturation in I-ON that was not present in F-I. In addition, the gain of I-ONdecreased sharply with increasing input conductance, resulting in much lower stretch-evoked firing rates in high-input conductance cells. All three of these phenomena (high initial gain, saturation, and differences in low- and high-input conductance cells) were also readily apparent in the differences between stretch-evoked I N,TOT and I N, PASS and thus could be accounted for by the activation of the dendritic PIC. As a result, stretch-evoked I N,TOT and F-I provided an accurate prediction of the overall change in stretch-evoked firing. However, in about half of the low-input conductance cells, the rate of rise of firing in response to stretch was not smoothly graded but instead consisted of a rapid surge. Stretch-evoked I N,TOT was always smoothly graded. This suggests that although stretch-evoked I N,TOT can be used to predict the overall change in firing, prediction of the dynamics of firing may be less accurate.