Adam S. Deardorff

Expression of postsynaptic Ca2+‐activated K+ (SK) channels at C‐bouton synapses in mammalian lumbar α‐motoneurons

Spinal cord α‐motoneurons display strong membrane immunoreactivity (IR) against small‐conductance calcium‐activated potassium channel (SK) isoform SK2, and a specific subpopulation of motoneurons also express SK3‐IR. Rat α‐motoneurons expressing SK3‐IR are significantly smaller, have significantly longer after‐hyperpolarization half‐decay time, significantly larger after‐hyperpolarization amplitude and significantly slower axon conduction velocity than α‐motoneurons that lack SK3‐IR. Motoneuron pools innervating slow‐twitch muscles have a higher percentage of SK3‐IR α‐motoneurons than those innervating fast‐twitch muscles. Expression of SK3 may contribute to variability in after‐hyperpolarization duration and amplitude across different types of rat α‐motoneurons and may be a molecular factor differentiating between slow‐ and fast‐type motoneurons. In the soma and proximal dendrites of α‐motoneurons, large clusters of SK2 and SK3 channel subunits appose cholinergic C‐boutons and colocalize with muscarinic type 2 receptors and Kv2.1 channels, which suggests a novel cellular mechanism for state‐dependent regulation of neuronal excitability.

Development of emotional intelligence in a team-based learning internal medicine clerkship.

Background: Although increasing number of articles have been published on team-based learning (TBL), none has explored team emotional intelligence. Aim: We extend the literature by examining changes in team emotional intelligence during a third year clerkship where TBL is a primary instructional strategy. We hypothesized that team emotional intelligence will change in a positive direction (i.e., increase) during the clerkship. Method: With IRB approval, during the 2009–2010 academic year third-year students in their internal medicine clerkship (N = 105, 100% response rate) completed the Workgroup Emotional Intelligence Profile – Short Version (WEIP-S) at the beginning and at the end of their 12-week clerkship. TBL is an instructional strategy utilized during the internal medicine clerkship. Results: Paired t-tests showed that team emotional intelligence increased significantly pre to post clerkship for three of the four areas: awareness of own emotions (p = 0.018), recognizing emotions in others (p = 0.031), and ability to manage others emotions (p = 0.013). There was no change for ability to control own emotions (p = 0.570). Conclusion: In an internal medicine clerkship, where TBL is utilized as an instructional strategy, team emotional intelligence increases. This supports TBL as an adjunctive tool to traditional medical education pedagogy.

Lateral superior olive function in congenital deafness

The development of cochlear implants for the treatment of patients with profound hearing loss has advanced considerably in the last few decades, particularly in the field of speech comprehension. However, attempts to provide not only sound decoding but also spatial hearing are limited by our understanding of circuit adaptations in the absence of auditory input. Here we investigate the lateral superior olive (LSO), a nucleus involved in interaural level difference (ILD) processing in the auditory brainstem using a mouse model of congenital deafness (the dn/dn mouse). An electrophysiological investigation of principal neurons of the LSO from the dn/dn mouse reveals a higher than normal proportion of single spiking (SS) neurons, and an increase in the hyperpolarisation-activated I(h) current. However, inhibitory glycinergic input to the LSO appears to develop normally both pre and postsynaptically in dn/dn mice despite the absence of auditory nerve activity. In combination with previous electrophysiological findings from the dn/dn mouse, we also compile a simple Hodgkin and Huxley circuit model in order to investigate possible computational deficits in ILD processing resulting from congenital hearing loss. We find that the predominance of SS neurons in the dn/dn LSO may compensate for upstream modifications and help to maintain a functioning ILD circuit in the dn/dn mouse. This could have clinical repercussions on the development of stimulation paradigms for spatial hearing with cochlear implants.

Sound stimulation modulates high-threshold K+ currents in mouse auditory brainstem neurons

The auditory system provides a valuable experimental model to investigate the role of sensory activity in regulating neuronal membrane properties. In this study, we have investigated the role of activity directly by measuring changes in medial nucleus of the trapezoid body (MNTB) neurons in normal hearing mice subjected to 1‐h sound stimulation. Broadband (4–12 kHz) chirps were used to activate MNTB neurons tonotopically restricted to the lateral MNTB, as confirmed by c‐Fos‐immunoreactivity. Following 1‐h sound stimulation a substantial increase in Kv3.1b‐immunoreactivity was measured in the lateral region of the MNTB, which lasted for 2 h before returning to control levels. Electrophysiological patch‐clamp recordings in brainstem slices revealed an increase in high‐threshold potassium currents in the lateral MNTB of sound‐stimulated mice. Current‐clamp and dynamic‐clamp experiments showed that MNTB cells from the sound‐stimulated mice were able to maintain briefer action potentials during high‐frequency firing than cells from control mice. These results provide evidence that acoustically driven auditory activity can selectively regulate high‐threshold potassium currents in the MNTB of normal hearing mice, likely due to an increased membrane expression of Kv3.1b channels.

Swimming against the tide: investigations of the C-bouton synapse

C-boutons are important cholinergic modulatory loci for state-dependent alterations in motoneuron firing rate. m2 receptors are concentrated postsynaptic to C-boutons, and m2 receptor activation increases motoneuron excitability by reducing the action potential afterhyperpolarization. Here, using an intensive review of the current literature as well as data from our laboratory, we illustrate that C-bouton postsynaptic sites comprise a unique structural/functional domain containing appropriate cellular machinery (a “signaling ensemble”) for cholinergic regulation of outward K+ currents. Moreover, synaptic reorganization at these critical sites has been observed in a variety of pathologic states. Yet despite recent advances, there are still great challenges for understanding the role of C-bouton regulation and dysregulation in human health and disease. The development of new therapeutic interventions for devastating neurological conditions will rely on a complete understanding of the molecular mechanisms that underlie these complex synapses. Therefore, to close this review, we propose a comprehensive hypothetical mechanism for the cholinergic modification of α-MN excitability at C-bouton synapses, based on findings in several well-characterized neuronal systems.

Redistribution of Kv2.1 ion channels on spinal motoneurons following peripheral nerve injury

Pathophysiological responses to peripheral nerve injury include alterations in the activity, intrinsic membrane properties and excitability of spinal neurons. The intrinsic excitability of α-motoneurons is controlled in part by the expression, regulation, and distribution of membrane-bound ion channels. Ion channels, such as Kv2.1 and SK, which underlie delayed rectifier potassium currents and afterhyperpolarization respectively, are localized in high-density clusters at specific postsynaptic sites (Deardorff et al., 2013; Muennich and Fyffe, 2004). Previous work has indicated that Kv2.1 channel clustering and kinetics are regulated by a variety of stimuli including ischemia, hypoxia, neuromodulator action and increased activity. Regulation occurs via channel dephosphorylation leading to both declustering and alterations in channel kinetics, thus normalizing activity (Misonou et al., 2004; Misonou et al., 2005; Misonou et al., 2008; Mohapatra et al., 2009; Park et al., 2006). Here we demonstrate using immunohistochemistry that peripheral nerve injury is also sufficient to alter the surface distribution of Kv2.1 channels on motoneurons. The dynamic changes in channel localization include a rapid progressive decline in cluster size, beginning immediately after axotomy, and reaching maximum within one week. With reinnervation, the organization and size of Kv2.1 clusters do not fully recover. However, in the absence of reinnervation Kv2.1 cluster sizes fully recover. Moreover, unilateral peripheral nerve injury evokes parallel, but smaller effects bilaterally. These results suggest that homeostatic regulation of motoneuron Kv2.1 membrane distribution after axon injury is largely independent of axon reinnervation.

Incentive structure in team-based learning: graded versus ungraded Group Application exercises

Purpose: Previous studies on team-based learning (TBL) in medical education demonstrated improved learner engagement, learner satisfaction, and academic performance; however, a paucity of information exists on modifications of the incentive structure of “traditional” TBL practices. The current study investigates the impact of modification to conventional Group Application exercises by examining student preference and student perceptions of TBL outcomes when Group Application exercises are excluded from TBL grades. Methods: During the 2009–2010 and 2010–2011 academic years, 175 students (95.6% response rate) completed a 22-item multiple choice survey followed by 3 open response questions at the end of their second year of medical school. These students had participated in a TBL supplemented preclinical curriculum with graded Group Application exercises during year one and ungraded Group Application exercises during year two of medical school. Results: Chi-square analyses showed significant differences between grading categories for general assessment of TBL, participation and communication, intra-team discussion, inter-team discussion, student perceptions of their own effort and development of teamwork skills. Furthermore, 83.8% of students polled prefer ungraded Group Application exercises with only 7.2% preferring graded and 9.0% indicating no preference. Conclusion: The use of ungraded Group Application exercises appears to be a successful modification of TBL, making it more “student-friendly” while maintaining the goals of active learning and development of teamwork skills.

Complex impairment of IA muscle proprioceptors following traumatic or neurotoxic injury

The health of primary sensory afferents supplying muscle has to be a first consideration in assessing deficits in proprioception and related motor functions. Here we discuss the role of a particular proprioceptor, the IA muscle spindle proprioceptor in causing movement disorders in response to either regeneration of a sectioned peripheral nerve or damage from neurotoxic chemotherapy. For each condition, there is a single preferred and widely repeated explanation for disability of movements associated with proprioceptive function. We present a mix of published and preliminary findings from our laboratory, largely from in vivo electrophysiological study of treated rats to demonstrate newly discovered IA afferent defects that seem likely to make important contributions to movement disorders. First, we argue that reconnection of regenerated IA afferents with inappropriate targets, although often repeated as the reason for lost stretch–reflex contraction, is not a complete explanation. We present evidence that despite successful recovery of stretch‐evoked sensory signaling, peripherally regenerated IA afferents retract synapses made with motoneurons in the spinal cord. Second, we point to evidence that movement disability suffered by human subjects months after discontinuation of oxaliplatin (OX) chemotherapy for some is not accompanied by peripheral neuropathy, which is the acknowledged primary cause of disability. Our studies of OX‐treated rats suggest a novel additional explanation in showing the loss of sustained repetitive firing of IA afferents during static muscle stretch. Newly extended investigation reproduces this effect in normal rats with drugs that block Na+ channels apparently involved in encoding static IA afferent firing. Overall, these findings highlight multiplicity in IA afferent deficits that must be taken into account in understanding proprioceptive disability, and that present new avenues and possible advantages for developing effective treatment. Extending the study of IA afferent deficits yielded the additional benefit of elucidating normal processes in IA afferent mechanosensory function.

Muscle proprioceptors in adult rat: mechanosensory signaling and synapse distribution in spinal cord

The characteristic signaling and intraspinal projections of muscle proprioceptors best described in the cat are often generalized across mammalian species. However, species-dependent adaptations within this system seem necessary to accommodate asymmetric scaling of length, velocity, and force information required by the physics of movement. In the present study we report mechanosensory responses and intraspinal destinations of three classes of muscle proprioceptors. Proprioceptors from triceps surae muscles in adult female Wistar rats anesthetized with isoflurane were physiologically classified as muscle spindle group Ia or II or as tendon organ group Ib afferents, studied for their firing responses to passive-muscle stretch, and in some cases labeled and imaged for axon projections and varicosities in spinal segments. Afferent projections and the laminar distributions of provisional synapses in rats closely resembled those found in the cat. Afferent signaling of muscle kinematics was also similar to reports in the cat, but rat Ib afferents fired robustly during passive-muscle stretch and Ia afferents displayed an exaggerated dynamic response, even after locomotor scaling was accounted for. These differences in mechanosensory signaling by muscle proprioceptors may represent adaptations for movement control in different animal species.NEW & NOTEWORTHY Muscle sensory neurons signal information necessary for controlling limb movements. The information encoded and transmitted by muscle proprioceptors to networks in the spinal cord is known in detail only for the cat, but differences in size and behavior of other species challenge the presumed generalizability. This report presents the first findings detailing specializations in mechanosensory signaling and intraspinal targets for functionally identified subtypes of muscle proprioceptors in the rat.

Activity-dependent redistribution of Kv2.1 ion channels on rat spinal motoneurons

Homeostatic plasticity occurs through diverse cellular and synaptic mechanisms, and extensive investigations over the preceding decade have established Kv2.1 ion channels as key homeostatic regulatory elements in several central neuronal systems. As in these cellular systems, Kv2.1 channels in spinal motoneurons (MNs) localize within large somatic membrane clusters. However, their role in regulating motoneuron activity is not fully established in vivo. We have previously demonstrated marked Kv2.1 channel redistribution in MNs following in vitro glutamate application and in vivo peripheral nerve injury (Romer et al., 2014, Brain Research, 1547:1–15). Here, we extend these findings through the novel use of a fully intact, in vivo rat preparation to show that Kv2.1 ion channels in lumbar MNs rapidly and reversibly redistribute throughout the somatic membrane following 10 min of electrophysiological sensory and/or motor nerve stimulation. These data establish that Kv2.1 channels are remarkably responsive in vivo to electrically evoked and synaptically driven action potentials in MNs, and strongly implicate motoneuron Kv2.1 channels in the rapid homeostatic response to altered neuronal activity.