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A method is described that, for the first time, allows instantaneous estimation of the Ia fiber input to human soleus motoneurons following electrical stimulation of the tibial nerve. The basis of the method is to determine the thresholds of the most and least excitable 1a fibers to electrical stimulation, and to treat the intervening thresholds as having a normal distribution about the mean; the validity of this approach is discussed. It was found that, for the same Ia fiber input, the percentage of soleus motoneurons contributing to the H (Hoffmann)-reflex differed considerably among subjects; when the results were pooled, however, there was an approximately linear relationship between Ia input and motoneuron output. Weak extension of the great toe diminished the soleus motoneuron reflex discharge in all but 2 of 16 subjects; the results for weak ankle plantarflexion were less consistent, but overall, there was a reduction in soleus motoneuron output also. The methodology should provide new insights into disorders of movement and tone, especially as it permits estimates of motoneuron depolarization to be made. NEW & NOTEWORTHY Assuming a normal distribution of Ia fiber thresholds to electrical stimulation and using the H-reflex, we determined for the first time an Ia input-α-motoneuron output relationship for the human soleus muscle. The relationship varies greatly among subjects but, overall, is approximately linear. Minimal contraction of a toe muscle alters the relationship dramatically, probably due to presynaptic inhibition of Ia fibers. Drawing on the literature, we can calculate changes in α-motoneuron membrane potential.

Dopaminergic modulation of prefrontal cortical activity is known to affect cognitive functions like working memory. Little consensus on the role of dopamine modulation has been achieved, however, in part because quantities directly relating to the neuronal substrate of working memory are difficult to measure. Here we show that dopamine increases the gain of the frequency-current relationship of layer 5 pyramidal neurons in vitro in response to noisy input currents. The gain increase could be attributed to a reduction of the slow afterhyperpolarization by dopamine. Dopamine also increases neuronal excitability by shifting the input-output functions to lower inputs. The modulation of these response properties is mainly mediated by D1 receptors. Integrate-and-fire neurons were fitted to the experimentally recorded input-output functions and recurrently connected in a model network. The gain increase induced by dopamine application facilitated and stabilized persistent activity in this network. The results support the hypothesis that catecholamines increase the neuronal gain and suggest that dopamine improves working memory via gain modulation.

We examined how hippocamal CA1 neurons process complex time-varying inputs that dendrites are likely to receive in vivo. We propose a functional model of the dendrite-to-soma input/output relationship that combines temporal integration and static-gain control mechanisms. Using simultaneous dual whole cell recordings, we injected 50 s of subthreshold and suprathreshold zero-mean white-noise current into the primary dendritic trunk along the proximal 2/3 of stratum radiatum and measured the membrane potential at the soma. Applying a nonlinear system-identification analysis, we found that a cascade of a linear filter followed by an adapting static-gain term fully accounted for the nonspiking input/output relationship between the dendrite and soma. The estimated filters contained a prominent band-pass region in the 1- to 10-Hz frequency range that remained constant as a function of stimulus variance. The gain of the dendrite-to-soma input/output relationship, in contrast, varied as a function of stimulus variance. When the contribution of the voltage-dependent current Ih was eliminated, the estimated filters lost their band-pass properties and the gain regulation was substantially altered. Our findings suggest that the dendrite-to-soma input/output relationship for proximal apical inputs to CA1 pyramidal neurons is well described as a band-pass filter in the theta frequency range followed by a gain-control nonlinearity that dynamically adapts to the statistics of the input signal.

Understanding the intrinsic membrane properties of juxtaglomerular (JG) cells is a necessary step toward understanding the neural basis of olfactory signal processing within the glomeruli. We used patch-clamp recordings and two-photon Ca2+imaging in rat olfactory bulb slices to analyze a long-lasting plateau potential generated in JG cells and characterize its functional input–output roles in the glomerular network. The plateau potentials were initially generated by dendritic calcium channels. Bath application of Ni2+(250 μM to 1 mM) totally blocked the plateau potential. A local puff of Ni2+on JG cell dendrites, but not on the soma, blocked the plateau potentials, indicating the critical contribution of dendritic Ca2+channels. Imaging studies with two-photon microscopy showed that a dendritic Ca2+increase was always correlated with a dendritic but not a somatic plateau potential. The dendritic Ca2+conductance contributed to boosting the initial excitatory postsynaptic potentials (EPSPs) to produce the plateau potential that shunted and reduced the amplitudes of the following EPSPs. This enables the JG cells to act as low-pass filters to convert high-frequency inputs to low-frequency outputs. The low frequency (2.6 ± 0.8 Hz) of rhythmic plateau potentials appeared to be determined by the intrinsic membrane properties of the JG cell. These properties of the plateau potential may enable JG cells to serve as pacemaker neurons in the synchronization and oscillation of the glomerular network.

A single spinal motoneuron receives tens of thousands of synapses. The neurotransmitters released by many of these synapses act on iontotropic receptors and alter the driving potential of neighboring synapses. This interaction introduces an intrinsic nonlinearity in motoneuron input–output properties where the response to two simultaneous inputs is less than the linear sum of the responses to each input alone. Our goal was to determine the impact of this nonlinearity on the current delivered to the soma during activation of predetermined numbers and distributions of excitatory and inhibitory synapses. To accomplish this goal we constructed compartmental models constrained by detailed measurements of the geometry of the dendritic trees of three feline motoneurons. The current “lost” as a result of local changes in driving potential was substantial and resulted in a highly nonlinear relationship between the number of active synapses and the current reaching the soma. Background synaptic activity consisting of a balanced activation of excitatory and inhibitory synapses further decreased the current delivered to the soma, but reduced the nonlinearity with respect to the total number of active excitatory synapses. Unexpectedly, simulations that mimicked experimental measures of nonlinear summation, activation of two sets of excitatory synapses, resulted in nearly linear summation. This result suggests that nonlinear summation can be difficult to detect, despite the substantial “loss” of current arising from nonlinear summation. The magnitude of this “loss” appears to limit motoneuron activity, based solely on activation of iontotropic receptors, to levels that are inadequate to generate functionally meaningful muscle forces.

Recent in vitro experiments revealed that the GABAA reversal potential is about 10 mV higher than the resting potential in mature mammalian neocortical pyramidal cells; thus GABAergic inputs could have facilitatory, rather than inhibitory, effects on action potential generation under certain conditions. However, how the relationship between excitatory input conductances and the output firing rate is modulated by such depolarizing GABAergic inputs under in vivo circumstances has not yet been understood. We examine herewith the input–output relationship in a simple conductance-based model of cortical neurons with the depolarized GABAA reversal potential, and show that a tonic depolarizing GABAergic conductance up to a certain amount does not change the relationship between a tonic glutamatergic driving conductance and the output firing rate, whereas a higher GABAergic conductance prevents spike generation. When the tonic glutamatergic and GABAergic conductances are replaced by in vivo–like highly fluctuating inputs, on the other hand, the effect of depolarizing GABAergic inputs on the input–output relationship critically depends on the degree of coincidence between glutamatergic input events and GABAergic ones. Although a wide range of depolarizing GABAergic inputs hardly changes the firing rate of a neuron driven by noncoincident glutamatergic inputs, a certain range of these inputs considerably decreases the firing rate if a large number of driving glutamatergic inputs are coincident with them. These results raise the possibility that the depolarized GABAA reversal potential is not a paradoxical mystery, but is instead a sophisticated device for discriminative firing rate modulation.

Intracellular recordings from association cortical areas 5 and 7 were performed in cats under barbiturate or ketamine-xylazine anesthesia to investigate the activities of different classes of neurons involved in callosal pathways, which were electrophysiologically characterized by depolarizing current steps. Excitatory postsynaptic potentials (EPSPs), inhibitory postsynaptic potentials (IPSPs), and/or antidromic responses were elicited by stimulating homotopic sites in the contralateral cortical areas. Differential features of EPSPs related to latencies, amplitudes, and slopes were detected in closely located (50 μm or less) neurons recorded in succession along the same electrode track. In contrast to synchronous thalamocortical volleys that excited most neurons within a cortical column, stimuli applied to homotopic sites in the contralateral cortex activated neurons at restricted cortical depths. Median latencies of callosally evoked EPSPs were 1.5 to 4 ms in various cortical cell-classes. Fast-rhythmic-bursting neurons displayed EPSPs whose amplitudes were threefold larger, and latencies two- or threefold shorter, than those found in the three other cellular classes. Converging callosal and thalamic inputs were recorded in the same cortical neuron. EPSPs or IPSPs were elicited by stimulating foci spaced by

1. The effects of different types of synaptic input on the steady-state input-output relations of the mammalian motoneuron pool were investigated by the use of computer simulations. The properties of the simulated motor units and their synaptic inputs were based as closely as possible on the experimental data from studies in the cat hindlimb. 2. Three basic types of synaptic input systems were simulated: postsynaptic, presynaptic, and neuromodulatory. The effects of these inputs on three aspects of the system input-output structure were studied: gain, precision, and motor-unit type utilization. 3. The gain analyses were based on a simulation of the steady-state homonymous Ia input. The gain of this steady-state Ia “reflex” was found to be determined largely by the slope of the pool input-output function. Precision was evaluated in two ways, from the amplitudes of the quantal steps due to motor-unit recruitment and from the sensitivity of the input-output function to noise. The pattern of motor-unit type utilization allowed indirect assessment of fatigue resistance: the larger the percentage of force generated by FF units, the lower the fatigue resistance. 4. A uniformly distributed input (i.e., one that generates equal input in all motoneurons) generates outputs that are solely determined by the intrinsic properties of the motor units. Thus the gain, precision, and motor-unit type patterns generated by a uniform input were used as the basis with which the effects of all other input systems were compared. 5. Postsynaptic excitatory inputs with nonuniform distributions within the pool did influence gain. The greatest effect was the increase mediated by the rubrospinal excitatory input (27% increase at 30% of maximal force). However, this input also greatly decreased both fatigue resistance and precision, due to increased activation of FF units at low force levels. In contrast, the Ia input slightly decreased gain (12% decrease at 30% of maximum force) while slightly increasing fatigue resistance and precision. 6. The simulated neuromodulatory input was based on the monoaminergic reticulospinal effect on motoneurons. Gain was generally increased by the monoaminergic input. However, the magnitude of the increase strongly depended on whether the monoaminergic effects were largest on S units (giving a 20% increase at 30% of maximum force), equal on all types (52%), or largest on FF units (102%). Presynaptic inhibition reduced gain with no effect whatsoever on fatigue resistance or precision. 7. Therefore Ia reflex gain was modifiable by all three types of input: postsynaptic, presynaptic, and neuromodulatory.(ABSTRACT TRUNCATED AT 400 WORDS)

1. A pool of 100 simulated motor units was constructed in which the steady-state neural and mechanical properties of the units were very closely matched to the available experimental data for the cat medial gastrocnemius motoneuron pool and muscle. The resulting neural network generated quantitative predictions of whole system input-output functions based on the single unit data. The results of the simulations were compared with experimental data on normal motor system behavior in humans and animals. 2. We considered only steady-state, isometric conditions. All motoneurons received equal proportions of the synaptic input, and no feedback loops were operative. Thus the intrinsic properties of the motor unit population alone determined the form of the system input-output function. Expressing the synaptic input in terms of effective synaptic current allowed the simulated motoneuron input-output functions to be specified by well-known firing rate-injected current relations. The motor unit forces were determined from standard motor unit force-frequency relations, and the system output at any input level was assumed to be the linear sum of the forces of the active motor units. 3. The steady-state input-output function of the simulated motoneuron pool had a roughly sigmoidal shape that was quite different from those derived from previous recruitment models, which did not incorporate frequency modulation. Frequency modulation in combination with the skewed distribution of thresholds (low values much more frequent than high) restricted upward curvature to low input levels, whereas frequency modulation alone was responsible for the final gradual approach to the maximum force output. 4. Sensitivity analyses were performed to assess the importance of several assumptions that were required to deal with gaps and uncertainties in the available experimental data. The shape of the input-output function was not critically dependent on any of these assumptions, including those specifying linear summation of inputs and outputs. 5. A key assumption of the model was that systematic variance in motor unit properties was much more important than random variance for determining the input-output function. Addition of random variance via Monte Carlo techniques showed that this assumption was correct. These results suggest that the output of a motoneuron pool should be quite tolerant of random variance in the distribution of synaptic inputs and yet substantially altered by any systematic differences, such as unequal distribution of inputs among different motor unit types.(ABSTRACT TRUNCATED AT 400 WORDS)

Populations of dendritic spines can change in number and shape quite rapidly as a result of synaptic activity. Here, we explore the consequences of such changes on the input–output properties of a dendritic branch. We consider two models: one for activity-dependent spine densities and the other for calcium-mediated spine-stem restructuring. In the activity-dependent density model we find that for repetitive synaptic input to passive spines, changes in spine density remain local to the input site. For excitable spines, the spine density increases both inside and outside the input region. When the spine stem resistances are relatively high, the transition to higher dendritic output is abrupt; when low, the rate of increase is gradual and resembles long-term potentiation. In the second model, spine density is held constant, but the stem dimensions are allowed to change as a result of stimulation-induced calcium influxes. The model is formulated so that a moderate amount of synaptic activation results in spine stem elongation, whereas high levels of activation result in stem shortening. Under these conditions, passive spines receiving modest stimulation progressively increase their spine stem resistance and head potentials, but little change occurs in the dendritic output. For excitable spines, modest stimulation frequencies cause a lengthening of both stimulated and neighboring spines and the stimulus eventually propagates. High-frequency stimulation that causes spines to shorten in the stimulated region decreases the amplitude of the dendritic output slightly or drastically, depending on initial spine densities and stem resistances.

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.

1. Somatosensory afferent input and its relationship with efferent output were examined in the primary face motor cortex (MI) and adjacent cerebral cortical areas. Excitatory afferent inputs were tested in a total of 1,654 single neurons recorded in awake or anesthetized monkeys (Macaca fascicularis), and output was characterized in these same monkeys by the movement and EMG responses evoked by intracortical microstimulation (ICMS) at the neuronal recording sites. 2. Most neurons in the MI area responded to light tactile stimulation of the orofacial region, especially the upper lip, lower lip, and tongue. Although contralateral afferent inputs predominated, 21% of the neurons received ipsilateral or bilateral orofacial inputs. The afferent input evoked by tactile stimulation of the upper and lower lips was represented especially at the medial border and the input from the tongue at the lateral border of MI. However, in most regions of MI between the medial and lateral borders, an intermingling of tactile inputs from different orofacial areas occurred. Multiple representation of tactile input from the same orofacial area was found in several, often quite separate, intracortical sites in MI. 3. Only a small proportion of the MI neurons could be activated by the deep stimuli used (e.g., stretch and pressure applied to muscle, passive jaw movement, low-intensity stimulation of hypoglossal nerve) from the orofacial region. Those neurons which did respond to these low-threshold deep inputs were not clearly segregated from those which responded to tactile input, although most of the neurons receiving deep input were located in the rostral part of MI. 4. A somatotopic pattern of representation of orofacial tactile input was more obvious in the primary face somatosensory cortex (SI). At the medial border of SI, the periorbital area was represented, then followed laterally in sequence the tactile representation of the upper lip, lower lip, and intraoral area. Contralateral afferent inputs predominated, but as in MI, a considerable proportion of SI neurons received ipsilateral or bilateral orofacial inputs. Few neurons in the region explored (areas 3b, 1, and 2) responded to deep orofacial stimuli. 5. Tactile input also dominated the input patterns of neurons in the premotor cortex (PM). Most neurons received ipsilateral or bilateral orofacial afferent inputs and no clear somatotopic pattern was noted. Several PM neurons were also activated by visual stimuli. 6. Muscle twitches evoked by ICMS were limited to MI.(ABSTRACT TRUNCATED AT 400 WORDS)