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K E Cullen

Publications and source records attributed to K E Cullen.

At least 19 recordsLinked to original sources
PubMed2004

Postural and locomotor control in normal and vestibularly deficient mice.

We investigated how vestibular information is used to maintain posture and control movement by studying vestibularly deficient mice (IsK-/- mutant). In these mutants, microscopy showed degeneration of the cristae of the semicircular canals and of the maculae of the utriculi and sacculi, while behavioural and vestibulo-ocular reflex testing showed that vestibular function was completely absent. However, the histology of Scarpa's ganglia and the vestibular nerves was normal in mutant mice, indicating the presence of intact central pathways. Using X-ray and high-speed cineradiography, we compared resting postures and locomotion patterns between these vestibularly deficient mice and vestibularly normal mice (wild-type and IsK+/-). The absence of vestibular function did not affect resting posture but had profound effects on locomotion. At rest, the S-shaped, sagittal posture of the vertebral column was the same for wild-type and mutant mice. Both held the head with the atlanto-occipital joint fully flexed, the cervico-thoracic junction fully flexed, and the cervical column upright. Wild-type mice extended the head and vertebral column and could walk in a straight line. In marked contrast, locomotion in vestibularly deficient mice was characterized by circling episodes, during which the vertebral column maintained an S-shaped posture. Thus, vestibular information is not required to control resting posture but is mandatory for normal locomotion. We propose that vestibular inputs are required to signal the completion of a planned trajectory because mutant mice continued rotating after changing heading direction. Our findings support the hypothesis that vertebrates limit the number of degrees of freedom to be controlled by adopting just a few of the possible skeletal configurations.

Animals↗
PubMed2004

Effects of electrode penetrations into the abducens nucleus of the monkey: eye movement recordings and histopathological evaluation of the nuclei and lateral rectus muscles.

Two adult rhesus monkeys that had undergone 2 years of electrode penetrations into their abducens and vestibular nuclei, for chronic eye movement studies, were examined histologically. An analysis of their VIth nucleus neurons and lateral rectus muscles revealed the following. Twenty-two percent of the large neurons (approximately 30 microm in diameter), on average, were missing and extensive neuropil disruption and gliosis was evident in the experimental side abducens nuclei as compared with the control side in each animal. While the lateral rectus muscles showed small, but inconsistent, changes in total fiber number, the muscle fiber diameters were altered, leading to a more homogenous muscle and making the typical orbital and global subdivisions of the muscle less distinct. Eye movement records from before and after the electrophysiological studies were comparable. We discuss how the complex architecture of the extraocular muscles as well as the possibility of polyneuronal innervation of single muscle fibers could explain our results.

Abducens Nerve↗
PubMed2001

Selective processing of vestibular reafference during self-generated head motion.

The vestibular sensory apparatus and associated vestibular nuclei are generally thought to encode head-in-space motion. Angular head-in-space velocity is detected by vestibular hair cells that are located within the semicircular canals of the inner ear. In turn, the afferent fibers of the vestibular nerve project to neurons in the vestibular nuclei, which, in head-restrained animals, similarly encode head-in-space velocity during passive whole-body rotation. However, during the active head-on-body movements made to generate orienting gaze shifts, neurons in the vestibular nuclei do not reliably encode head-in-space motion. The mechanism that underlies this differential processing of vestibular information is not known. To address this issue, we studied vestibular nuclei neural responses during passive head rotations and during a variety of tasks in which alert rhesus monkeys voluntarily moved their heads relative to space. Neurons similarly encoded head-in-space velocity during passive rotations of the head relative to the body and during passive rotations of the head and body together in space. During all movements that were generated by activation of the neck musculature (voluntary head-on-body movements), neurons were poorly modulated. In contrast, during a task in which each monkey actively "drove" its head and body together in space by rotating a steering wheel with its arm, neurons reliably encoded head-in-space motion. Our results suggest that, during active head-on-body motion, an efferent copy of the neck motor command, rather than the monkey's knowledge of its self-generated head-in-space motion or neck proprioceptive information, gates the differential processing of vestibular information at the level of the vestibular nuclei.

Action Potentials↗
PubMed2001

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Health Personnel↗
PubMed2001

Signal processing by vestibular nuclei neurons is dependent on the current behavioral goal.

The vestibular sensory apparatus and associated vestibular nuclei are generally thought to encode angular head velocity during our daily activities. However, in addition to direct inputs from vestibular afferents, the vestibular nuclei receive substantial projections from cortical, cerebellar, and other brainstem structures. Given this diversity of inputs, the question arises: How are the responses of vestibular nuclei neurons to head velocity modified by these additional inputs during naturally occurring behaviors? Here we have focused on the signal processing done by two specific classes of neurons in the vestibular nuclei: (1) position-vestibular-pause (PVP) neurons that mediate the vestibulo-ocular reflex (VOR), and (2) vestibular-only (VO) neurons that are thought to mediate, at least in part, the vestibulo-collic reflex (VCR). We first characterized neuronal responses to passive rotation in the head-restrained condition, and then released the head to record the discharges of the same neurons during self-generated head movements. VOR interneurons (i.e., PVP neurons) faithfully transmitted head velocity signals when the animal stabilized its gaze, regardless of whether the head motion was actively or passively generated; their responses were attenuated only when the monkey's behavioral goal was to redirect its axis of gaze relative to space. In contrast, VCR interneurons (i.e., VO neurons) faithfully transmitted head velocity signals during passive head motion, but their responses were greatly (and similarly) attenuated during all behaviors (i.e., gaze shifts, gaze pursuit, gaze stabilization) during which the monkey's behavioral goal was to move its head relative to the body. To characterize the mechanism(s) that underlie this differential processing, we tested neurons during passive rotation of the head relative to the body, as well as during a task in which a monkey actively "drove" both its head and body together in space. We conclude that neither passive activation of neck proprioceptors nor knowledge of self-generated head-in-space motion directly mediate the observed reductions in head-velocity-related modulation. Instead, we propose that the VOR and VCR pathways use efference copies of oculomotor and neck movement commands, respectively, for the differential processing of vestibular information.

Action Potentials↗
PubMed2000

A comparison of head-unrestrained and head-restrained pursuit: influence of eye position and target velocity on latency.

Horizontal step-ramp target trajectories were used to study the initiation of head-unrestrained and head-restrained pursuit in the monkey. In a first series of experiments, initial target position (0 degrees, 5 degrees, or 30 degrees, contraversive to the direction of pursuit), fixation duration, target velocity (20 degrees, 40 degrees, 60 degrees and 80 degrees/s), and target direction were randomized in order to minimize predictive responses. Animals pursued the target either with their eyes alone (head-restrained: HR condition) or with a combination of eye and head movements (head-unrestrained: HU condition). Head motion onset consistently lagged pursuit onset (i.e., eye motion) by 50 ms or more in the HU condition, and was influenced by target velocity as well as by initial target position. Pursuit onset latencies did not vary systematically as a function of target velocity in either the HR or HU conditions. However, pursuit initiation latencies tended to be longer in the HU condition as compared to the HR condition when target motion started from the most contraversive position. A second series of experiments revealed that this difference in HR and HU pursuit onset latencies could be explained by the effects of initial eye-in-head position; more contraversive initial eye positions yielded shorter pursuit latencies in both conditions, and the monkeys generally moved their head towards the target in the HU condition, resulting in smaller eye-in-head eccentricities. Furthermore, we found that initial gaze and head positions had little or no effect on pursuit latencies. We conclude that the latency for pursuit initiation is similar irrespective of whether an animal is head-restrained or head-unrestrained, when initial eye position is held constant.

Animals↗
PubMed2000

Comparing extraocular motoneuron discharges during head-restrained saccades and head-unrestrained gaze shifts.

Burst neurons (BNs) in the paramedian pontine reticular formation provide the primary input to the extraocular motoneurons (MNs) during head-restrained saccades and combined eye-head gaze shifts. Prior studies have shown that BNs carry eye movement-related signals during saccades and carry head as well as eye movement-related signals during gaze shifts. Therefore MNs receive signals related to head motion during gaze shifts, yet they solely drive eye motion. Here we addressed whether the relationship between MN firing rates and eye movements is influenced by the additional premotor signals present during gaze shifts. Neurons in the abducens nucleus of monkeys were first studied during saccades made with the head stationary. We then recorded from the same neurons during voluntary combined eye-head gaze shifts. We conclude that the activity of MNs, in contrast to that of BNs, is related to eye motion by the same dynamic relationship during head-restrained saccades and head-unrestrained gaze shifts. In addition, we show that a standard metric-based analysis [i.e., counting the number of spikes (NOS) in a burst] yields misleading results when applied to the same data set. We argue that this latter approach fails because it does not properly consider the system's dynamics or the strong interactions between eye and head motion.

Animals↗
PubMed1999

Quantitative analysis of abducens neuron discharge dynamics during saccadic and slow eye movements.

The mechanics of the eyeball and its surrounding tissues, which together form the oculomotor plant, have been shown to be the same for smooth pursuit and saccadic eye movements. Hence it was postulated that similar signals would be carried by motoneurons during slow and rapid eye movements. In the present study, we directly addressed this proposal by determining which eye movement-based models best describe the discharge dynamics of primate abducens neurons during a variety of eye movement behaviors. We first characterized abducens neuron spike trains, as has been classically done, during fixation and sinusoidal smooth pursuit. We then systematically analyzed the discharge dynamics of abducens neurons during and following saccades, during step-ramp pursuit and during high velocity slow-phase vestibular nystagmus. We found that the commonly utilized first-order description of abducens neuron firing rates (FR = b + kE + r, where FR is firing rate, E and are eye position and velocity, respectively, and b, k, and r are constants) provided an adequate model of neuronal activity during saccades, smooth pursuit, and slow phase vestibular nystagmus. However, the use of a second-order model, which included an exponentially decaying term or "slide" (FR = b + kE + r + uE - c), notably improved our ability to describe neuronal activity when the eye was moving and also enabled us to model abducens neuron discharges during the postsaccadic interval. We also found that, for a given model, a single set of parameters could not be used to describe neuronal firing rates during both slow and rapid eye movements. Specifically, the eye velocity and position coefficients (r and k in the above models, respectively) consistently decreased as a function of the mean (and peak) eye velocity that was generated. In contrast, the bias (b, firing rate when looking straight ahead) invariably increased with eye velocity. Although these trends are likely to reflect, in part, nonlinearities that are intrinsic to the extraocular muscles, we propose that these results can also be explained by considering the time-varying resistance to movement that is generated by the antagonist muscle. We conclude that to create realistic and meaningful models of the neural control of horizontal eye movements, it is essential to consider the activation of the antagonist, as well as agonist motoneuron pools.

Abducens Nerve↗
PubMed1998

A neural correlate for vestibulo-ocular reflex suppression during voluntary eye-head gaze shifts.

The vestibulo-ocular reflex (VOR) is classically associated with stabilizing the visual world on the retina by producing an eye movement of equal and opposite amplitude to the motion of the head. Here we have directly measured the efficacy of VOR pathways during voluntary combined eye-head gaze shifts by recording from individual vestibular neurons in monkeys whose heads were unrestrained. We found that the head-velocity signal carried by VOR pathways is reduced during gaze shifts in an amplitude-dependent manner, consistent with results from behavioral studies in humans and monkeys. Our data support the hypothesis that the VOR is not a hard-wired reflex, but rather a pathway that is modulated in a manner that depends on the current gaze strategy.

Animals↗
PubMed1997

Characterization of hypothermia-induced cellular stress response in mouse tissues.

Cells respond to adverse environmental conditions by expressing heat shock proteins, which serve to protect cells from harmful effects of the stress conditions. In this study we demonstrated that mice subjected to whole body hypothermia induced the cellular stress response, resulting in the increased expression of hsp72 mRNA in brain, heart, kidney, liver, and lung. We performed a detailed analysis of the major parameters of the stress response and found that cold induction of hsp expression is mediated by heat shock factor 1 (HSF1), which is also responsible for heat induction of the cellular stress response. However, there are differences in the mechanisms of HSF1 activation by hypothermia versus hyperthermia, as hypothermia does not cause the hyperphosphorylation of HSF1 that is characteristic of heat-activated HSF1.

Animals↗
PubMed1997

Regulation of hsp expression during rodent spermatogenesis.

Spermatogenesis is the process by which immature male germ cells, through a complex series of events involving mitosis, meiosis, and cellular differentiation, eventually become mature spermatozoa capable of fertilizing an ovum. This process involves the developmental progression of male germ cells through a number of spermatogenetic cell types, each of which is characterized by unique features of morphology, cellular associations, and specialized functions. The unique features of each germ cell type are dictated, to a large degree, by the patterns of protein expression characteristic of each cell type. This review will examine two different aspects of the regulated expression of heat shock proteins in spermatogenic cells. First, we will review studies showing that the expression of several different members of both the hsp70 as well as hsp90 families of heat shock proteins is regulated during the differentiation of these cells. Second, we will review studies which have examined the induction of hsp expression in spermatogenic cells following exposure to elevated temperatures. Next, we will review the role of the transcription factors, heat shock factor 1 (HSF1) and HSF2 in the regulation of expression of hsps in the testis. One interesting and unique function of the male reproductive system in many species is the maintenance of the testes at a temperature below that of the other tissues of the animal. The importance of precise thermoregulation of the testis is evidenced by the fact that even slight elevations of scrotal temperature are associated with infertility. The results of recent studies have suggested a potential involvement of the cellular stress response in the mechanism responsible for these inhibitory effects of elevated testis temperature on spermatogenesis. Possible mechanisms are discussed.

Animals↗
PubMed1997

Analysis of primate IBN spike trains using system identification techniques. I. Relationship To eye movement dynamics during head-fixed saccades.

The dynamic behavior of primate (Macaca fascicularis) inhibitory burst neurons (IBNs) during head-fixed saccades was analyzed by using system identification techniques. Neurons were categorized as IBNs on the basis of their anatomic location as well as by their activity during horizontal head-fixed saccadic and smooth pursuit eye movements and vestibular nystagmus. Each IBN's latency or "dynamic lead time" (td) was determined by shifting the unit discharge in time until an optimal fit to the firing rate frequency B(t) profile was obtained by using the simple model based on eye movement dynamics,B(t) = r + b1(t); where is eye velocity. For the population of IBNs, the dynamic estimate of lead time provided a significantly lower value than a method that used the onset of the first spike. We then compared the relative abilities of different eye movement-based models to predict B(t) by using objective optimization algorithms. The most important terms for predicting B(t) were eye velocity gain (b1) and bias terms (r) mentioned above. The contributions of higher-order velocity, acceleration, and/or eye position terms to model fits were found to be negligible. The addition of a pole term [the time derivative of B(t)] in conjunction with an acceleration term significantly improved model fits to IBN spike trains, particularly when the firing rates at the beginning of each saccade [initial conditions (ICs)] were estimated as parameters. Such a model fit the data well (a fit comparable to a linear regression analysis with a R2 value of 0.5, or equivalently, a correlation coefficient of 0.74). A simplified version of this model [B(t) = rk + b1(t)], which did not contain a pole term, but in which the bias term (rk) was estimated separately for each saccade, provided nearly equivalent fits of the data. However, models in which ICs or rks were estimated separately for each saccade contained too many parameters to be considered as useful models of IBN discharges. We discovered that estimated ICs and rks were correlated with saccade amplitude for the majority of short-lead IBNs (SLIBNs; 56%) and many long-lead IBNs (LLIBNs; 42%). This observation led us to construct a more simple model that included a term that was inversely related to the amplitude of the saccade, in addition to eye velocity and constant bias terms. Such a model better described neuron discharges than more complex models based on a third-order nonlinear function of eye velocity. Given the small number of parameters required by this model (only 3) and its ability to fit the data, we suggest that it provides the most valuable description of IBN discharges. This model emphasizes that the IBN discharges are dependent on saccade amplitude and implies further that a mechanism must exist, at the motoneuron (MN) level, to offset the effect of the bias and amplitude-dependent terms. In addition, we did not find a significant difference in the variance accounted for by any of the downstream models tested for SLIBNs versus LLIBNs. Therefore we conclude that the eye movement signals encoded dynamically by SLIBNs and LLIBNs are similar in nature. Put another way, SLIBNs are not closer, dynamically, to MNs than LLIBNs.

Action Potentials↗
PubMed1997

Analysis of primate IBN spike trains using system identification techniques. II. Relationship to gaze, eye, and head movement dynamics during head-free gaze shifts.

We have investigated the relationships among the firing frequency B(t) of inhibitory burst neurons (IBNs) and the metrics and dynamics of the eye, head, and gaze (eye + head) movements generated during voluntary combined eye-head gaze shifts in monkey. The same IBNs were characterized during head-fixed saccades in our first of three companion papers. In head-free gaze shifts, the number of spikes (NOS) in a burst was, for 82% of the neurons, better correlated with gaze amplitude than with the amplitude of either the eye or head components of the gaze shift. A multiple regression analysis confirmed that NOS was well correlated to the sum of head and eye amplitudes during head-free gaze shifts. Furthermore, the mean slope of the relationship between NOS and gaze amplitude was significantly less for head-free gaze shifts than for head-fixed saccades. NOS is a global parameter. To refine we used system identification techniques to evaluate a series of dynamic models in which IBN spike trains were related to gaze or eye movements. We found that gaze- and eye-based models predicted the discharges of IBNs equally well. However, the bias values required by gaze-based models were comparable to those required in our head-fixed models whereas those required by eye-based models were significantly larger. The difference in biases between gaze- and eye-based models was very strongly correlated to the mean head velocity () during gaze shifts [R = -0.93 +/- 0.15 (SD)]. This result suggested that the increased bias required by the eye-based models reflected an unmodeled input onto these cells. To pursue this argument further we investigated a series of dynamic models that included both eye velocity () and terms and this confirmed the importance of these two terms. As in our head-fixed analysis of companion paper I, the most valuable model formulation also included an eye saccade amplitude term (DeltaE) and was given by B(t) = r0 + r1DeltaE + b1 + g1 where r0, r1, b1, and g1 are constants. The amplitude of the head velocity coefficient was significantly less than that of the eye velocity coefficient. Furthermore, in our population long-lead IBNs tended to have a smaller head velocity coefficients than short-lead IBNs. We conclude that during head-free gaze shifts, the head velocity signal carried to the abducens nucleus by primate excitatory burst neurons (EBNs; if EBNs and IBNs carry similar signals) must be offset by other premotor cells.

Action Potentials↗
PubMed1997

Analysis of primate IBN spike trains using system identification techniques. III. Relationship To motor error during head-fixed saccades and head-free gaze shifts.

The classic model of saccade generation assumes that the burst generator is driven by a motor-error signal, the difference between the actual eye position and the final "desired" eye position in the orbit. Here we evaluate objectively, using system identification techniques, the dynamic relationship between motor-error signals and primate inhibitory burst neuron (IBN) discharges (upstream analysis). The IBNs presented here are the same neurons whose downstream relationships were characterized during head-fixed saccades and head-free gaze shifts in our companion papers. In our analysis of head-fixed saccades we determined how well IBN discharges encode eye motor error (epsilone) compared with downstream saccadic eye movement dynamics and whether long-lead IBN (LLIBN) discharges encode epsilone better than short-lead IBNs (SLIBNs), given that it is commonly assumed that short-lead burst neurons (BNs) are closer than long-lead BNs to the motor output and thus further from the epsilone signal. In the epsilone-based models tested, IBN firing frequency B(t) was represented by one of the following: 1) model 1u, a nonlinear function of epsilone; 2) model 2u, a linear function of epsilone [B(t) = rk + a1epsilone(t)] where the bias term rk was estimated separately for each saccade; 3) model 3u, a version of model 2u wherein the bias term was a function of saccade amplitude; or 4) model 4u, a linear function of epsilone with an added pole term (the derivative of firing rate). Models based on epsilone consistently produced worse predictions of IBN activity than models of comparable complexity based on eye movement dynamics (e.g., eye velocity). Hence, the simple two parameter downstream model 2d [B(t) = r + b1(t)] was much better than any upstream (epsilone-based) model with a comparable number of parameters. The link between B(t) and epsilone is due primarily to the correlation between the declining phases of B(t) and epsilone; motor-error models did not predict well the rising phase of the discharge. We could improve substantially the performance of upstream models by adding an e term. Because e = -, this process was equivalent to incorporating terms into upstream models thereby erasing the distinction between upstream and downstream analyses. Adding an e term to the upstream models made them as good as downstream ones in predicting B(t). However, the epsilone term now became redundant because its removal did not affect model accuracy. Thus, when is available as a parameter, epsilone becomes irrelevant. In the head-free monkey the ability of upstream models to predict IBN firing during head-free gaze shifts when gaze, eye, or head motor-error signals were model inputs was poor and similar to the upstream analysis of the head-fixed condition. We conclude that during saccades (head-fixed) or gaze shifts (head-free) the activity of both SLIBNs and LLIBNs is more closely linked to downstream events (i.e., the dynamics of ongoing movements) than to the coincident upstream motor-error signal. Furthermore, SLIBNs and LLIBNs do not differ in their characteristics; the latter are not, as is usually hypothesized, closer to a motor-error signal than the former.

Animals↗
PubMed1996

The use of system identification techniques in the analysis of oculomotor burst neuron spike train dynamics.

The objective of system identification methods is to construct a mathematical model of a dynamical system in order to describe adequately the input-output relationship observed in that system. Over the past several decades, mathematical models have been employed frequently in the oculomotor field, and their use has contributed greatly to our understanding of how information flows through the implicated brain regions. However, the existing analyses of oculomotor neural discharges have not taken advantage of the power of optimization algorithms that have been developed for system identification purposes. In this article, we employ these techniques to specifically investigate the "burst generator" in the brainstem that drives saccadic eye movements. The discharge characteristics of a specific class of neurons, inhibitory burst neurons (IBNs) that project monosynaptically to ocular motoneurons, are examined. The discharges of IBNs are analyzed using different linear and nonlinear equations that express a neuron's firing frequency and history (i.e., the derivative of frequency), in terms of quantities that describe a saccade trajectory, such as eye position, velocity, and acceleration. The variance accounted for by each equation can be compared to choose the optimal model. The methods we present allow optimization across multiple saccade trajectories simultaneously. We are able to investigate objectively how well a specific equation predicts a neuron's discharge pattern as well as whether increasing the complexity of a model is justifiable. In addition, we demonstrate that these techniques can be used both to provide an objective estimate of a neuron's dynamic latency and to test whether a neuron's initial firing rate (expressed as an initial condition) is a function of a quantity describing a saccade trajectory (such as initial eye position).

Action Potentials↗