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Somatosensory-motor hindbrain neurons for the control of reaching movements
Full text linkForelimb movements are abundant in our daily movements, and range from simple (swatting a bug) to sophisticated (catching a ball). Between higher and lower motor control centers sits the brainstem region lateral rostral medulla (latRM), which is required for the execution of sophisticated reaching movements. To date, latRM has been largely considered a relay between motor cortex and spinal cord, but questions remain whether these neurons participate in additional computations. In Chapter 1, I present a review of existing literature related to motor control, with particular focus on what is known about brainstem premotor regions, including latRM. In Chapter 2, I present work investigating additional, non-premotor features of latRM reach-related neurons in the context of a novel innate, touch-evoked reaching behavioral paradigm in mice. Experiments demonstrate that latRM neurons, previously implicated in skilled forelimb reaching behaviors, are also required for innate reaching behaviors and, unexpectedly, respond to orofacial somatosensory stimuli. Through a combination of electrophysiological recordings, anatomical tracing, and inhibition experiments we show that somatosensory-motor latRM neurons receive ascending somatosensory information as well as top-down inputs from both motor cortex and the midbrain structure superior colliculus. Together, these findings suggest additional functions for latRM by acting as a site of convergence for multiple streams of sensory and motor information, thus expanding our understanding of the organization of brainstem motor control circuitry
History of Spinal Cord “Pain” Pathways Including the Pathways Not Taken
Full text linkTraditional medical neuroanatomy/neurobiology textbooks teach that pain is generated by several ascending pathways that course in the anterolateral quadrant of the spinal cord, including the spinothalamic, spinoreticular and spinoparabrachial tracts. The textbooks also teach, building upon the mid-19th century report of Brown-Séquard, that unilateral cordotomy, namely section of the anterolateral quadrant, leads to contralateral loss of pain (and temperature). In many respects, however, this simple relationship has not held up. Most importantly, pain almost always returns after cordotomy, indicating that activation of these so-called "pain" pathways may be sufficient to generate pain, but they are not necessary. Indeed, Brown-Séquard, based on his own studies, eventually came to the same conclusion. But his new view of "pain" pathways was largely ignored, and certainly did not forestall Spiller and Martin's 1912 introduction of cordotomy to treat patients. This manuscript reviews the history of "pain" pathways that followed from the first description of the Brown-Séquard Syndrome and concludes with a discussion of multisynaptic spinal cord ascending circuits. The latter, in addition to the traditional oligosynaptic "pain" pathways, may be critical to the transmission of "pain" messages, not only in the intact spinal cord but also particularly after injury
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
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The Influence of Mu Opioid Receptor Endocytosis on the Analgesic and Motivational Properties of Acute and Chronic Morphine
Full text linkThe biological actions of morphine and other opioid narcotics are mediated primarily by the mu opioid receptor (MOR). In response to endogenous opioids, the signaling of the MOR is regulated by a conserved endocytic mechanism, involving both the desensitization of signaling by receptor phosphorylation and arrestin recruitment and the subsequent resensitization by endocytosis and recycling. In response to morphine, however, this regulatory mechanism is only weakly engaged, resulting in persistent MOR desensitization without resensitization in some cells and in persistent MOR activation without desensitization in others. We hypothesized that this could have multiple consequences for morphine's physiological effects. First, persistent MOR desensitization, arising within minutes to days of morphine administration, could contribute to acutely diminished sensitivity to morphine and acute tolerance. Second, compensatory adaptations in response to persistent MOR activation, arising within hours to weeks of morphine administration, could contribute to chronic tolerance, physical dependence, and possibly addiction. To test this hypothesis, we generated a mutant Recycling MOR (RMOR) that desensitizes, internalizes, and recycles in response to morphine. Here, we describe the phenotype of knock-in mice expressing the mutant RMOR in place of the wild-type receptor. Consistent with our hypothesis, RMOR mice exhibited increased analgesia and reward selectively in response to morphine. Furthermore, they developed reduced tolerance and physical dependence following chronic morphine treatment, and they were less likely to progress from controlled to compulsive drug seeking when given the opportunity to freely self-administer morphine. These results suggest that promoting agonist-induced MOR desensitization and endocytosis preserves the therapeutically desirable effects of opioid drugs while preventing their negative side effects, particularly tolerance, physical dependence, and addiction
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The cellular logic of pain modality discrimination
Full text linkNoxious stimuli are detected by primary afferent neurons of the dorsal root ganglia (DRG). Such neurons, known as nociceptors, can be divided into several distinct populations based on the heterogeneous distribution of receptors, ion channels, and neurotransmitters, however, functional correlates of these anatomical differences are yet unidentified. The work in this thesis further examines the neurochemical and functional segregation of nociceptor subtypes through a genetic and pharmacological investigation of neurons that express the heat and capsaicin receptor, TRPV1. TRPV1 is activated by noxious heat stimuli (>43 °C), and is robustly expressed by primary afferent nociceptors. In addition, some have argued that TRPV1 is widely distributed in cells outside of the DRG, although there is considerable disagreement as to the extent and localization of this expression. To address this question, we generated a line of mice in which TRPV1 + cells co-express two reporter genes: placental alkaline phosphatase and nuclear lacZ. These enzymes allow for the sensitive and accurate identification of TRPV1+ cells and processes. Using this approach, we observed that, in contrast to numerous previous reports, TRPV1 expression in the nervous system is largely limited to peptidergic, primary afferent neurons. We additionally found evidence for TRPV1 in arteriolar smooth muscle cells, highlighting an important substrate for the actions of heat, protons, and other TRPV1 agonists on vascular tone. We then investigated the relative contribution of TRPV1+ and TRPV1- nociceptors to the behavioral responses to stimuli of different pain modalities. Surprisingly, despite the fact that most nociceptors show polymodal response properties in electrophysiological assays, we found that pharmacological ablation of the central branches of TRPV1+ nociceptors selectively abolished heat pain sensitivity without altering behavioral responses to mechanical or cold stimuli. Conversely, we found that genetic ablation of nociceptors expressing the G protein-coupled receptor, MrgprD, which marks a large subset of TRPV1- DRG neurons, selectively reduced behavioral sensitivity to noxious mechanical stimuli. This double-dissociation suggests that the brain can distinguish different noxious stimulus modalities from the earliest stages of sensory processing as a result of distinct contributions from molecularly-defined nociceptor subtypes
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Prefrontal neurocardiac networks during approach-avoidance behaviors
Full text linkAnimals engage in approach-avoidance behaviors when confronted with potentially threatening cues. These behaviors are supported by neural computations and peripheral reactions in the body, such as autonomic signals that give rise to the classic “fight-or-flight” response. Significant changes in heart rate during these situations are a hallmark of this response. Importantly, the brain exerts top-down control over cardiac activity and heart rate can also influence brain function. Fluctuations in heart rate modulate neural activity in the medial prefrontal cortex (mPFC), a region involved in evaluating social environments, anxiogenic contexts, and guiding adaptive decisions. However, how cardiac signals are mapped in the mPFC during approach-avoidance behaviors remains unclear. To address this, we developed a multidisciplinary approach to simultaneously record heart rate and measure single-cell calcium signals from mPFC neurons in freely moving mice navigating social and anxiogenic contexts. This approach revealed neural ensembles in the mPFC that encode heart rate, which we termed “neurocardiac networks.” We hypothesized that activity in these neurons would decouple from heart rate in anxiogenic or social contexts that promote avoidance because the mPFC may prioritize threat evaluation or decision-making over interoceptive monitoring. Indeed, neurocardiac networks became decoupled when mice approached an aggressive mouse, but not a juvenile mouse. Moreover, decoupling increased when mice navigated environments thought to induce higher anxiety levels. Our findings provide a new framework for identifying functionally distinct neurons in the mPFC using heart rate as a physiological readout, advancing our mechanistic understanding of how brain-heart interactions shape social and anxiety-related behaviors
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Behavioral measures of persistent pain in mice
Full text linkThe use of animal models in the understanding of the neurobiology of pain perception is essential for the development of new pharmacotherapies. Yet, in modeling human clinical experience, there is a lack of meaningful and appropriate dependent variables of pain-related behaviors in the mouse. In this thesis, we address the problem of finding behavioral measures of pain in mice that fully encompass the range of experience inherent to human pain conditions. Therefore, in this work complex behaviors were assessed as potential measures of persistent pain in miceWe investigated a wide range of quality of life behaviors in three classic pain models: spared nerve injury, chronic constriction injury and injection of complete Freund's adjuvant. Mechanical hypersensitivity is prominent in each of these conditions and persists for many weeks. To assess more complex behavioral outcomes, home cage behavior was continuously monitored after injury and a battery of motor disability and affective behavior tests were performed on these mice. No model of chronic pain produced long-lasting changes to behaviors of daily life, either in the home cage or in tests of affect and disability.Next, we observed behaviors in three other models of persistent pain: osteoarthritis, disc-degeneration, and dental pulp exposure. In a pilot study of the former two models, mice with joint degeneration were tested for locomotor ability and motivation, but showed no signs of disability. Lastly, we measured behavior in the setting of dental pulp inflammation, for which there is no standard method of measuring pain levels. As with other models, pulpal injury also did not impact behavior in the home cage. Instead, we used an operant assay of sucrose consumption as a measure of dental pain in mice. Data from this task suggest that pain can, in fact, influence some elements of complex behavior. However, as alteration in daily life activities is the feature that is so disrupted in patients with chronic pain, our results suggest that many murine pain models do not fully reflect the human conditions and raise questions regarding the limitations of these models in pain research
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