Final Common Path Research Articles

Hypothalamic CRF neurons facilitate brain reward function

Aversive stimuli activate corticotropin-releasing factor (CRF)-expressing neurons in the paraventricular nucleus of hypothalamus (PVNCRF neurons) and other brain stress systems to facilitate avoidance behaviors. Appetitive stimuli also engage the brain stress systems, but their contributions to reward-related behaviors are less well understood. Here, we show that mice work vigorously to optically activate PVNCRF neurons in an operant chamber, indicating a reinforcing nature of these neurons. The reinforcing property of these neurons is not mediated by activation of the hypothalamic-pituitary-adrenal (HPA) axis. We found that PVNCRF neurons send direct projections to the ventral tegmental area (VTA), and selective activation of these projections induced robust self-stimulation behaviors, without activation of the HPA axis. Similar to the PVNCRF cell bodies, self-stimulation of PVNCRF-VTA projection was dramatically attenuated by systemic pretreatment of CRF receptor 1 or dopamine D1 receptor (D1R) antagonist and augmented by corticosterone synthesis inhibitor metyrapone, but not altered by dopamine D2 receptor (D2R) antagonist. Furthermore, we found that activation of PVNCRF-VTA projections increased c-Fos expression in the VTA dopamine neurons and rapidly triggered dopamine release in the nucleus accumbens (NAc), and microinfusion of D1R or D2R antagonist into the NAc decreased the self-stimulation of these projections. Together, our findings reveal an unappreciated role of PVNCRF neurons and their VTA projections in driving reward-related behaviors, independent of their core neuroendocrine functions. As activation of PVNCRF neurons is the final common path for many stress systems, our study suggests a novel mechanism underlying the positive reinforcing effect of stressful stimuli.

THU650 Prevalence Of Hyperandrogenemia, PCOS And Obesity In Mothers Of Daughters With PCOS

Abstract Disclosure: J. Cai: None. K. Brewer: None. R. Sisk: None. R.S. Legro: None. A.E. Dunaif: None. Prenatal exposure to androgens produces phenocopies of PCOS in animal models. In mice, there is evidence for transgenerational prenatal androgen effects. Human studies considered to support the hypothesis that intrauterine actions of androgens play a major role in PCOS pathogenesis come from (1) health registries where PCOS in mothers and daughters was diagnosed by ICD codes and (2) retrospective assessment of mother’s PCOS status in cohorts of affected women. Maternal PCOS status has not been directly assessed. As part of our genetic analyses of PCOS, we have prospectively recruited 678 mothers and 540 fathers of 678 women fulfilling NIH criteria for PCOS with confirmed hyperandrogenism and ovulatory dysfunction (OD). All subjects had fasting blood samples for reproductive hormones measured in central labs. Mothers completed a validated questionnaire for reproductive history. We tested the hypothesis that maternal PCOS accounted for PCOS in her daughter. We also investigated the contribution of maternal compared to paternal obesity to daughters’ obesity. We limited the analysis to mothers age 50 yrs and younger, with FSH <40 mIU/mL; 108 fathers were available from these families. Continuous data are reported as median and data range. Age (yrs): daughters 23 (13-24), mothers 46 (34-50), fathers 48 (37-69). Daughters had significantly higher BMI (kg/m2) (35.3, 18.5-60.0) than mothers (28.9, 18.7-54.1) and fathers (29.6, 18.4-55.5) (both P <0 .0001), while BMI did not differ in mothers and fathers. Hyperandrogenemia (HA), defined as total testosterone >58 ng/dL, biologically available testosterone >15 ng/dL or DHEAS >2683ng/mL, was present in 14.4% (20/139) of mothers, of these, 2.2% (3/139) fulfilled NIH criteria for PCOS, HA+OD. The prevalence of obesity, BMI ≥ 30.0 kg/m2, (66.2% daughter, 44.8% mother, and 45.7% fathers) was increased in daughters compared to both mothers (p= 0.0004) and fathers (p< 0.0001). Mothers with HA had higher BMI than those without it (P= 0.011). The odds ratio for obesity in daughters was 5.16 (1.97, 13.48) with maternal obesity and 2.29 (0.95, 5.52) with paternal obesity. Only ∼14% of reproductive-age mothers had HA, which we have shown in an underlying reproductive phenotype in PCOS families (Legro. Proc Natl Acad Sci USA, 1998); ∼ 2% of mothers fulfilled NIH criteria for PCOS. Although the PCOS reproductive phenotype ameliorates with age, it is clear that many affected daughters did not have a mother with hormonal features of PCOS. These findings do not support the hypothesis that prenatal androgen exposure is a final common path to PCOS in humans. The prevalence of obesity was higher in daughters than in parents and in HA mothers compared mothers without HA suggesting that obesity was associated with features of PCOS. Maternal obesity conferred greater risk for obesity in daughters than paternal obesity. Presentation: Thursday, June 15, 2023

The priming effect of rewarding brain stimulation in rats depends on both the cost and strength of reward but survives blockade of D2-like dopamine receptors.

Receipt of an intense reward boosts motivation to work for more of that reward. This phenomenon is called the priming effect of rewards. Using a novel measurement method, we show that the priming effect of rewarding electrical brain stimulation depends on the cost, as well as on the strength, of the anticipated reward. Previous research on the priming effect of electrical brain stimulation utilized a runway paradigm in which running speed serves as the measure of motivation. In the present study, the measure of motivation was the vigour with which rats executed a two-lever response chain, in a standard operant-conditioning chamber, to earn rewarding electrical stimulation of the lateral hypothalamus. In a second experiment, we introduced a modification that entails self-administered priming stimulation and alternating blocks of primed and unprimed trials. Reliable, consistent priming effects of substantial magnitude were obtained in the modified paradigm, which is closely analogous to the runway paradigm. In a third experiment, the modified paradigm served to assess the dependence of the priming effect on dopamine D2-like receptors. The priming effect proved resilient to the effect of eticlopride, a selective D2-like receptor antagonist. These results are discussed within the framework of a new model of brain reward circuitry in which non-dopaminergic medial forebrain bundle fibers and dopamine axons provide parallel inputs to the final common paths for reward and incentive motivation.

Cardiomyocyte electrophysiology and its modulation: current views and future prospects.

Normal and abnormal cardiac rhythms are of key physiological and clinical interest. This introductory article begins from Sylvio Weidmann's key historic 1950s microelectrode measurements of cardiac electrophysiological activity and Singh & Vaughan Williams's classification of cardiotropic targets. It then proceeds to introduce the insights into cardiomyocyte function and its regulation that subsequently emerged and their therapeutic implications. We recapitulate the resulting view that surface membrane electrophysiological events underlying cardiac excitation and its initiation, conduction and recovery constitute the final common path for the cellular mechanisms that impinge upon this normal or abnormal cardiac electrophysiological activity. We then consider progress in the more recently characterized successive regulatory hierarchies involving Ca2+ homeostasis, excitation-contraction coupling and autonomic G-protein signalling and their often reciprocal interactions with the surface membrane events, and their circadian rhythms. Then follow accounts of longer-term upstream modulation processes involving altered channel expression, cardiomyocyte energetics and hypertrophic and fibrotic cardiac remodelling. Consideration of these developments introduces each of the articles in this Phil. Trans. B theme issue. The findings contained in these articles translate naturally into recent classifications of cardiac electrophysiological targets and drug actions, thereby encouraging future iterations of experimental cardiac electrophysiological discovery, and testing directed towards clinical management. This article is part of the theme issue 'The heartbeat: its molecular basis and physiological mechanisms'.

Dopamine and Beyond: Implications of Psychophysical Studies of Intracranial Self-Stimulation for the Treatment of Depression.

Major depressive disorder is a leading cause of disability and suicide worldwide. Consecutive rounds of conventional interventions are ineffective in a significant sub-group of patients whose disorder is classified as treatment-resistant depression. Significant progress in managing this severe form of depression has been achieved through the use of deep brain stimulation of the medial forebrain bundle (MFB). The beneficial effect of such stimulation appears strong, safe, and enduring. The proposed neural substrate for this promising clinical finding includes midbrain dopamine neurons and a subset of their cortical afferents. Here, we aim to broaden the discussion of the candidate circuitry by exploring potential implications of a new “convergence” model of brain reward circuitry in rodents. We chart the evolution of the new model from its predecessors, which held that midbrain dopamine neurons constituted an obligatory stage of the final common path for reward seeking. In contrast, the new model includes a directly activated, non-dopaminergic pathway whose output ultimately converges with that of the dopaminergic neurons. On the basis of the new model and the relative ineffectiveness of dopamine agonists in the treatment of depression, we ask whether non-dopaminergic circuitry may contribute to the clinical efficacy of deep brain stimulation of the MFB.

Demographic and Epidemiological Profile of Aging and Elderly Patients Receiving Heart Transplant During the Period from 2009 to 2018

Background: The aging process may be associated with the accumulation of a wide variety of health damages, such as cardiovascular diseases. HF is the final common path of the majority of these diseases, and, in its refractory form, heart transplantation continues to be the best treatment choice. Objective: To describe the demographic and epidemiological profile of aging and elderly patients receiving heart transplant from 2009 to 2018. Methods: Retrospective, descriptive longitudinal study on heart transplantation in aging and elderly [...]

The Convergence Model of Brain Reward Circuitry: Implications for Relief of Treatment-Resistant Depression by Deep-Brain Stimulation of the Medial Forebrain Bundle

Deep-brain stimulation of the medial forebrain bundle (MFB) can provide effective, enduring relief of treatment-resistant depression. Panksepp provided an explanatory framework: the MFB constitutes the core of the neural circuitry subserving the anticipation and pursuit of rewards: the “SEEKING” system. On that view, the SEEKING system is hypoactive in depressed individuals; background electrical stimulation of the MFB alleviates symptoms by normalizing activity. Panksepp attributed intracranial self-stimulation to excitation of the SEEKING system in which the ascending projections of midbrain dopamine neurons are an essential component. In parallel with Panksepp’s qualitative work, intracranial self-stimulation has long been studied quantitatively by psychophysical means. That work argues that the predominant directly stimulated substrate for MFB self-stimulation are myelinated, non-dopaminergic fibers, more readily excited by brief electrical current pulses than the thin, unmyelinated axons of the midbrain dopamine neurons. The series-circuit hypothesis reconciles this view with the evidence implicating dopamine in MFB self-stimulation as follows: direct activation of myelinated MFB fibers is rewarding due to their trans-synaptic activation of midbrain dopamine neurons. A recent study in which rats worked for optogenetic stimulation of midbrain dopamine neurons challenges the series-circuit hypothesis and provides a new model of intracranial self-stimulation in which the myelinated non-dopaminergic neurons and the midbrain dopamine projections access the behavioral final common path for reward seeking via separate, converging routes. We explore the potential implications of this convergence model for the interpretation of the antidepressant effect of MFB stimulation. We also discuss the consistent finding that psychomotor stimulants, which boost dopaminergic neurotransmission, fail to provide a monotherapy for depression. We propose that non-dopaminergic MFB components may contribute to the therapeutic effect in parallel to, in synergy with, or even instead of, a dopaminergic component.

Electrical Properties of Adult Mammalian Motoneurons.

Motoneurons are the 'final common path' between the central nervous system (that intends, selects, commands, and organises movement) and muscles (that produce the behaviour). Motoneurons are not passive relays, but rather integrate synaptic activity to appropriately tune output (spike trains) and therefore the production of muscle force. In this chapter, we focus on studies of mammalian motoneurons, describing their heterogeneity whilst providing a brief historical account of motoneuron recording techniques. Next, we describe adult motoneurons in terms of their passive, transition, and active (repetitive firing) properties. We then discuss modulation of these properties by somatic (C-boutons) and dendritic (persistent inward currents) mechanisms. Finally, we briefly describe select studies of human motor unit physiology and relate them to findings from animal preparations discussed earlier in the chapter. This interphyletic approach to the study of motoneuron physiology is crucial to progress understanding of how these diverse neurons translate intention into behaviour.

Dopamine neurons do not constitute an obligatory stage in the final common path for the evaluation and pursuit of brain stimulation reward.

The neurobiological study of reward was launched by the discovery of intracranial self-stimulation (ICSS). Subsequent investigation of this phenomenon provided the initial link between reward-seeking behavior and dopaminergic neurotransmission. We re-evaluated this relationship by psychophysical, pharmacological, optogenetic, and computational means. In rats working for direct, optical activation of midbrain dopamine neurons, we varied the strength and opportunity cost of the stimulation and measured time allocation, the proportion of trial time devoted to reward pursuit. We found that the dependence of time allocation on the strength and cost of stimulation was similar formally to that observed when electrical stimulation of the medial forebrain bundle served as the reward. When the stimulation is strong and cheap, the rats devote almost all their time to reward pursuit; time allocation falls off as stimulation strength is decreased and/or its opportunity cost is increased. A 3D plot of time allocation versus stimulation strength and cost produces a surface resembling the corner of a plateau (the "reward mountain"). We show that dopamine-transporter blockade shifts the mountain along both the strength and cost axes in rats working for optical activation of midbrain dopamine neurons. In contrast, the same drug shifted the mountain uniquely along the opportunity-cost axis when rats worked for electrical MFB stimulation in a prior study. Dopamine neurons are an obligatory stage in the dominant model of ICSS, which positions them at a key nexus in the final common path for reward seeking. This model fails to provide a cogent account for the differential effect of dopamine transporter blockade on the reward mountain. Instead, we propose that midbrain dopamine neurons and neurons with non-dopaminergic, MFB axons constitute parallel limbs of brain-reward circuitry that ultimately converge on the final-common path for the evaluation and pursuit of rewards.

An ePIC Assessment of Quadriceps Motor Unit Firing Patterns During Isometric Knee Extension: A High Density Surface Electromyography Study

Motor neurons (MNs) are the ‘final common path’ through which all motor commands must converge to generate motor output. MN firing patterns are readily accessible in humans due to the one‐to‐one spike ratio between MNs and the muscle fibers that they innervate. MNs are, therefore, the only neurons in the body in which the firing patterns can be directly associated with functional behaviors. Observed firing patterns vary systematically across the muscles of the human body, reflecting the interplay between the synaptic organization of motor commands, structure of the musculoskeletal system, and diversity of motor tasks. The goal of our lab is to develop a “human motor output map”, using newly developed high‐density surface electromyography (EMG) array electrodes that discriminate motor unit firing patterns based on convolutive blind source separation. Two main advantages of these arrays are: 1) the relatively high motor unit yield, and 2) the fact that motor units can be recorded with minimally invasive methods. We estimate the level of neuromodulatory drive (estimated persistent inward current, i.e. ePIC) to MNs using the well‐established paired motor unit analysis technique, which compares the onset and offset of a high‐threshold motor unit with respect to a low‐threshold unit and quantifies discharge rate hysteresis (ΔF). Preliminary studies in our lab suggest a strong proximal to distal gradient along the arm for motor unit firing patterns. Proximal muscles (i.e. Anterior Deltoid, Triceps Brachii, and Biceps Brachii) generate motor unit firing patterns consistent with high neuromodulatory drive (i.e. ΔF = ~4–6 spikes/s), whereas distal muscles (i.e. finger flexors or extensors, and intrinsic hand muscles) show lower neuromodulatory drive (i.e. ΔF = ~2–3 spikes/s). In the legs, the ankle dorsi‐ and plantarflexors generate motor unit firing patterns with moderate neuromodulatory drive (i.e. ΔF = ~3–5 spikes/s). However, it is unknown whether the proximal to distal gradient found in the arm also occurs in the leg. In the present study, we used high‐density surface EMG arrays to decompose motor unit firing patterns of three of the four quadriceps muscles: vastus lateralis, rectus femoris, and vastus medialis oblique. Decomposition of the EMG yielded ~7 motor units per trial, which is fewer than the decomposed motor unit yield of the lower leg, though still considerably higher than more traditional in‐dwelling EMG electrodes used for motor unit discrimination. Our data indicate that activation of the quadriceps generates motor unit firing patterns consistent with moderate neuromodulatory drive (i.e. ΔF = ~3.5 spikes/s), similar to the more distal muscles. These findings suggest that the proximal to distal gradient in motor unit firing patterns observed in the upper limbs is not analogous in the lower limbs of humans, likely reflecting the differences in functional organization between the arms and legs in bipeds.

Advanced interventional cardiac procedures and perioperative care required to prevent the epidemic of end-stage heart disease in Sri Lanka

Cardiovascular disease is the the leading cause of morbidity and mortality in the world and in Sri Lanka. This epidemic with multiple aetiologies lead to a final common path of heart failure, which can be averted by timely delivery of state-of-the art interventional cardiac procedures. The expansion of Primary PCI, complex coronary interventions for ischaemic heart disease with calcific vessels and CTO using Rotablation, Transcatheter heart valve (TAVI/Mitraclip) procedures for valve disease, Intracoronary transplantation of autologous stem cells for failing hearts, septal ablations and multiple device therapies for congenital heart diseases are examples of the discussed novel interventional cardiac therapies that are gaining pace as treatment modalities available for complex cardiac patients in Sri Lanka.

Investigating the Mitochondrial Permeability Transition Pore in Disease Phenotypes and Drug Screening.

Mitochondria act as ‘sinks’ for Ca2+ signaling, with mitochondrial Ca2+ uptake linking physiological stimuli to increased ATP production. However, mitochondrial Ca2+ overload can induce a cellular catastrophe by opening of the mitochondrial permeability transition pore (mPTP). This pore is a large conductance pathway in the inner mitochondrial membrane that causes bioenergetic collapse and appears to represent a final common path to cell death in many diseases. The role of the mPTP as a determinant of disease outcome is best established in ischemia/reperfusion injury in the heart, brain, and kidney, and it is also implicated in neurodegenerative disorders and muscular dystrophies. As the probability of pore opening can be modulated by drugs, it represents a useful pharmacological target for translational research in drug discovery. Described in this unit is a protocol utilizing isolated mitochondria to quantify this phenomenon and to develop a high‐throughput platform for phenotypic screens for Ca2+ dyshomeostasis. © 2019 The Authors. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Understanding exercise-dependent plasticity of motoneurons using intracellular and intramuscular approaches.

Spinal motoneurons (MN) exhibit exercise-dependent adaptations to increased activity, such as exercise and locomotion, as well as decreased activity associated with disuse, spinal cord injury, and aging. The development of several experimental approaches, in both human and animal models, has contributed significantly to our understanding of this plasticity. The purpose of this review is to summarize how intracellular recordings in an animal model and motor unit recordings in a human model have, together, contributed to our current understanding of exercise-dependent MN plasticity. These approaches and techniques will allow neuroscientists to continue to advance our understanding of MN physiology and the plasticity of the "final common path" of the motor system, and to design experiments to answer the critical questions that are emerging in this field.

The Spinal Cord, Not to Be Forgotten: the Final Common Path for Development, Training and Recovery of Motor Function.

Research on learning, memory, and neural plasticity has long focused on the brain. However, the spinal cord also exhibits these phenomena to a remarkable degree. Following a spinal cord injury, the isolated spinal cord in vivo can adapt to the environment and benefit from training. The amount of plasticity or recovery of function following a spinal injury often depends on the age at which the injury occurs. In this overview, we discuss learning in the spinal cord, including associative conditioning, neural mechanisms, development, and applications to clinical populations. We take an integrated approach to the spinal cord, one that combines basic and experimental information about experience-dependent learning in animal models to clinical treatment of spinal cord injuries in humans. From such an approach, an important goal is to better inform therapeutic treatments for individuals with spinal cord injuries, as well as develop a more accurate and complete account of spinal cord and behavioral functioning.

PERMA and the building blocks of well-being

Seligman (2011) hypothesized that PERMA (Positive Emotion, Engagement, Relationships, Meaning, and Accomplishment) are the elements of well-being. Goodman, Disabato, Kashdan & Kaufmann (2017) reported strong evidence that subjective well-being is the final common path of such elements and their data are entirely consistent with Seligman’s hypothesis. They argued, incorrectly however, that he suggested that PERMA constituted a different kind of well-being rather than just its building blocks. The complicated issue, one that transcends psychometrics, of how to decide on elements of well-being is discussed.

Tonically Active α5GABAA Receptors Reduce Motoneuron Excitability and Decrease the Monosynaptic Reflex.

Motoneurons, the final common path of the Central Nervous System (CNS), are under a complex control of its excitability in order to precisely translate the interneuronal pattern of activity into skeletal muscle contraction and relaxation. To fulfill this relevant function, motoneurons are provided with a vast repertoire of receptors and channels, including the extrasynaptic GABAA receptors which have been poorly investigated. Here, we confirmed that extrasynaptic α5 subunit-containing GABAA receptors localize with choline acetyltransferase (ChAT) positive cells, suggesting that these receptors are expressed in turtle motoneurons as previously reported in rodents. In these cells, α5GABAA receptors are activated by ambient GABA, producing a tonic shunt that reduces motoneurons’ membrane resistance and affects their action potential firing properties. In addition, α5GABAA receptors shunted the synaptic excitatory inputs depressing the monosynaptic reflex (MSR) induced by activation of primary afferents. Therefore, our results suggest that α5GABAA receptors may play a relevant physiological role in motor control.

S49 Changes in the final common path in CMT1A and RLS

Patients suffering from Charcot-Marie-Tooth disease complain about various so called positive and negative symptoms. Positive symptoms include e.g. paraesthesia, pain, fasciculations, muscle cramps and restless legs syndrome, whereby negative symptoms represent a loss of function, e.g. hypaesthesia or muscle weakness. There is growing knowledge about disease specific molecular pathomechanisms, which does not necessarily explain symptoms patients are complaining about. Currently there is no mechanism based treatment of any symptom. In this presentation I will give an overview about recent findings in Charcot-Marie-Tooth disease type 1A patients deciphering the mechanisms of motor symptoms, e.g. fasciculations, muscle cramps and regarding restless legs syndrome: leg movements and the urge to move. By combining axonal excitability studies with multi-unit electromyography recordings it is possible to decipher the role of changes in axonal excitability for the output of individual motor units and consequently also for motor symptoms. Our findings suggest that ion channel modulators may be beneficial to influence both positive and negative motor symptoms in CMT1A.

Antiepileptogenic repair of excitatory and inhibitory synaptic connectivity after neocortical trauma.

The "final common path" to epileptogenesis induced by cortical trauma and disease processes ultimately depends on changes in relative weights of excitatory and inhibitory synaptic activities in neuronal networks. Results of two experiments summarized here provide proof in principle that prophylaxis of posttraumatic epileptogenesis can result when antiepileptogenic treatments are focused on basic underlying synaptic mechanisms. (1) Brief gabapentin treatment after injury limits new excitatory synapse formation by preventing binding of thrombospondins to α2δ-1 receptors, resulting in long-lasting effects that limit aberrant excitatory connectivity and decrease epileptogenesis. (2) Fast-spiking (FS) interneurons are structurally and functionally abnormal in the partial cortical isolation and other models of epileptogenesis. Brain-derived neurotrophic factor (BDNF) supports growth and maintenance of GABAergic neurons during brain development, leading to the hypothesis that it might favorably affect injured interneurons. Partial activation of BDNF TrkB receptors with a small molecule reverses structural abnormalities in FS interneuronal terminals, increases the frequency of mIPSCs, and increases probability of GABA release. These changes are associated with significantly reduced spontaneous and evoked epileptiform bursts in vitro and increased threshold for pentylenetetrazole-induced seizures in vivo. Each of these treatments offers a potential promising approach to prophylaxis of injury-induced cortical epileptogenesis.

Isolation and Identification of ER Associated Proteins with Unique Expression Changes Specific to the V144D SPTLC1 Mutations in HSN-I

Axonal degeneration is the final common path in many neurological disorders. Hereditary sensory neuropathies (HSN) are a group of neuropathies involving the sensory neurons. The most common subtype is autosomal dominant hereditary sensory neuropathy type I (HSN-I). Progressive degeneration of the dorsal root ganglion (DRG) neuron with an onset of clinical symptoms between the second or third decade of life characterises HSN-I. Mutations in the serine palmitoyltransferase (SPT) long chain subunit 1 (SPTLC1) gene cause HSN-I. The endoplasmic reticulum (ER) is a dynamic organelle that houses the SPTLC1 protein. Ultra structural analysis has shown the ER in the HSN-I mutant cells to wrap around dysfunctional mitochondria and tethers them to the perinucleus. This investigation establishes that the V144D mutant of SPTLC1 alters the expression of and potentially interacts with a set of proteins within the ER. Using ER protein lysates from HSN-I patient and control lymphoblasts: we have identified a change in regulation of five proteins; Hypoxia Up regulated Protein 1: Chloride intracellular channel protein 1: Ubiqutin-40s Ribosomal protein S27a: Coactosin and Ig Kappa chain C. The expression and regulation of these proteins may help to establish a link between the ER and the ‘dying back’ process of the DRG neuron.

Treadmill training induced lumbar motoneuron dendritic plasticity and behavior recovery in adult rats after a thoracic contusive spinal cord injury

Spinal cord injury (SCI) is devastating, causing sensorimotor impairments and paralysis. Persisting functional limitations on physical activity negatively affect overall health in individuals with SCI. Physical training may improve motor function by affecting cellular and molecular responses of motor pathways in the central nervous system (CNS) after SCI. Although motoneurons form the final common path for motor output from the CNS, little is known concerning the effect of exercise training on spared motoneurons below the level of injury. Here we examined the effect of treadmill training on morphological, trophic, and synaptic changes in the lumbar motoneuron pool and on behavior recovery after a moderate contusive SCI inflicted at the 9th thoracic vertebral level (T9) using an Infinite Horizon (IH, 200 kDyne) impactor. We found that treadmill training significantly improved locomotor function, assessed by Basso–Beattie–Bresnahan (BBB) locomotor rating scale, and reduced foot drops, assessed by grid walking performance, as compared with non-training. Additionally, treadmill training significantly increased the total neurite length per lumbar motoneuron innervating the soleus and tibialis anterior muscles of the hindlimbs as compared to non-training. Moreover, treadmill training significantly increased the expression of a neurotrophin brain-derived neurotrophic factor (BDNF) in the lumbar motoneurons as compared to non-training. Finally, treadmill training significantly increased synaptic density, identified by synaptophysin immunoreactivity, in the lumbar motoneuron pool as compared to non-training. However, the density of serotonergic terminals in the same regions did not show a significant difference between treadmill training and non-training. Thus, our study provides a biological basis for exercise training as an effective medical practice to improve recovery after SCI. Such an effect may be mediated by synaptic plasticity, and neurotrophic modification in the spared lumbar motoneuron pool caudal to a thoracic contusive SCI.