The impact of glial inhibition on the spinal instrumental learning paradigm

Although neural plasticity has traditionally been studied within the brain, evidence indicates that the spinal cord is quite plastic as well. Spinal neurons can even support a simple form of instrumental learning (Grau et al., 1998), as indicated by spinally transected rats’ ability to exhibit an increase in hind limb flexion duration when limb extension is associated with shock (controllable shock). If limb extension is not associated with shock (uncontrollable shock), a learning deficit develops. Recent research indicates that other forms of plasticity, such as long-term potentiation and central sensitization, do not depend on neural activity alone, but also on glial cells. I examined whether glial cells are also necessary in spinal instrumental learning and the learning deficit. Therefore, two glial inhibitors were selected: minocycline and fluorocitrate. To examine the role of glial cells in spinal instrumental learning, rats received intrathecal minocycline, fluorocitrate, or saline prior to testing with 30-minutes of controllable leg-shock. Results indicate that both drugs dose-dependently reduced acquisition, with higher doses resulting in shorter response durations. Once the response was acquired, fluorocitrate did not alter response maintenance. This suggests that glial cells are involved in the acquisition, but not the maintenance, of spinal learning. To examine the role of glial cells in the spinal learning deficit rats were given intrathecal minocycline, fluorocitrate, or saline prior to testing with 6-minutes of uncontrollable tail shock or no shock. Twenty-four hours later all rats were tested with 30-minutes of controllable leg-shock. Results indicated the learning deficit induced by uncontrollable shock was prevented by prior administration of fluorocitrate. Minocycline did not prevent the deficit; moreover, it appears that even in the absence of shock, minocycline caused a learning deficit. Overall, this data indicate that glial cells are necessary for the acquisition of spinal instrumental learning and the learning deficit. Furthermore, it provides further evidence for the role of glial cells in plasticity

The Impact of Social Stress on Central Nervous System Inflammation and T Cell Response to Theiler’s Virus Infection

A growing body of evidence suggests that social stress contributes to the pathogenesis of neurodegenerative diseases, such as multiple sclerosis (MS). For example, prior research has shown that social disruption (SDR) stress behaviorally and immunologically exacerbates Theiler’s murine encephalomyelitis virus (TMEV) infection. TMEV infection results in acute infection of the central nervous system (CNS) followed by a chronic demyelinating autoimmune disease, similar to that seen in MS. Research suggests that social stress exerts these effects by altering the immune response to infection. More specifically, it is hypothesized that SDR sensitizes the acute inflammatory response to infection and suppresses T cell effector function in the acute phase of disease. It was demonstrated that SDR is sufficient to alter inflammation. Exposure to a single session of SDR increases IL-­‐1β mRNA expression; however, IL-­‐6 mRNA expression, but not IL-­‐1β, is up regulated in response to chronic SDR. Furthermore, chronic SDR prior to infection resulted in increased infection related central IL-­‐6 and IL-­‐1β mRNA expression, and central administration of IL-­‐6 neutralizing antibody during SDR reverses this increase in neuroinflammation. This suggests that SDR sensitizes infection related CNS inflammation through an up-­‐regulation of IL-­‐6. Chronic SDR prior to infection also resulted in enhanced CNS viral titers and suppression of virus-­‐induced CD4 and CD8 T cell IFN-­‐γ release within the CNS. As a whole, this research indicates that SDR exacerbates the disease course of TMEV infection by altering the central innate and adaptive immune response to infection. This research enhances our understanding of the mechanisms by which social stress exacerbates neurodegenerative disease pathogenesis

AAPT Diagnostic Criteria for Chronic Cancer Pain Conditions

Chronic cancer pain is a serious complication of malignancy or its treatment. Currently, no comprehensive, universally accepted cancer pain classification system exists. Clarity in classification of common cancer pain syndromes would improve clinical assessment and management. Moreover, an evidence-based taxonomy would enhance cancer pain research efforts by providing consistent diagnostic criteria, ensuring comparability across clinical trials. As part of a collaborative effort between the Analgesic, Anesthetic, and Addiction Clinical Trial Translations Innovations Opportunities and Networks (ACTTION) and the American Pain Society (APS), the ACTTION-APS Pain Taxonomy (AAPT) initiative worked to develop the characteristics of an optimal diagnostic system.59, 65 Following the establishment of these characteristics, a working group consisting of clinicians and clinical and basic scientists with expertise in cancer and cancer-related pain was convened to generate core diagnostic criteria for an illustrative sample of 3 chronic pain syndromes associated with cancer (i.e., bone pain and pancreatic cancer pain as models of pain related to a tumor) or its treatment (i.e., chemotherapy-induced peripheral neuropathy). A systematic review and synthesis was conducted to provide evidence for the dimensions that comprise this cancer pain taxonomy. Future efforts will subject these diagnostic categories and criteria to systematic empirical evaluation of their feasibility, reliability and validity and extension to other cancer-related pain syndromes

Glial Tumor Necrosis Factor Alpha (TNFα) Generates Metaplastic Inhibition of Spinal Learning

Injury-induced overexpression of tumor necrosis factor alpha (TNFα) in the spinal cord can induce chronic neuroinflammation and excitotoxicity that ultimately undermines functional recovery. Here we investigate how TNFα might also act to upset spinal function by modulating spinal plasticity. Using a model of instrumental learning in the injured spinal cord, we have previously shown that peripheral intermittent stimulation can produce a plastic change in spinal plasticity (metaplasticity), resulting in the prolonged inhibition of spinal learning. We hypothesized that spinal metaplasticity may be mediated by TNFα. We found that intermittent stimulation increased protein levels in the spinal cord. Using intrathecal pharmacological manipulations, we showed TNFα to be both necessary and sufficient for the long-term inhibition of a spinal instrumental learning task. These effects were found to be dependent on glial production of TNFα and involved downstream alterations in calcium-permeable AMPA receptors. These findings suggest a crucial role for glial TNFα in undermining spinal learning, and demonstrate the therapeutic potential of inhibiting TNFα activity to rescue and restore adaptive spinal plasticity to the injured spinal cord. TNFα modulation represents a novel therapeutic target for improving rehabilitation after spinal cord injury

The search for translational pain outcomes to refine analgesic development: Where did we come from and where are we going?

Pain measures traditionally used in rodents record mere reflexes evoked by sensory stimuli; the results thus may not fully reflect the human pain phenotype. Alterations in physical and emotional functioning, pain-depressed behaviors and facial pain expressions were recently proposed as additional pain outcomes to provide a more accurate measure of clinical pain in rodents, and hence to potentially enhance analgesic drug development. We aimed to review how preclinical pain assessment has evolved since the development of the tail flick test in 1941, with a particular focus on a critical analysis of some nonstandard pain outcomes, and a consideration of how sex differences may affect the performance of these pain surrogates. We tracked original research articles in Medline for the following periods: 1973-1977, 1983-1987, 1993-1997, 2003-2007, and 2014-2018. We identified 606 research articles about alternative surrogate pain measures, 473 of which were published between 2014 and 2018. This indicates that preclinical pain assessment is moving toward the use of these measures, which may soon become standard procedures in preclinical pain laboratories.FPU grant from the Spanish Ministry of Education, Culture and SportsSpanish Ministry of Economy and Competitiveness (MINECO, grant SAF2016-80540-R)Ramón Areces FoundationJunta de Andalucía (grant CTS 109)Esteve PharmaceuticalsEuropean Regional Development Fund (ERDF

(De)contextualising Buddhist aesthetics

(De)contextualising Buddhist Aesthetics is a practice-led artistic research project focusing on the interchanging transition between Buddhist and artistic practices. Essentially inspired by the concept of vipassanā meditation, I created a series of performances involving repetitive actions centring on the tasks of re-arranging readymade objects into multiple precarious configurations. Many exercises challenge the laws of gravity and other physical limitations of objects, as well as encouraging the learning experience through the process of trial and error. During the course of mindful observation of the performing body and objects, the mental state gradually gains moments of stillness and silence, which approach the meaning of emptiness (suññatā) in Buddhism. Repeated failures generate intermittent feelings of exhaustion and disappointment, which naturally become part of the progress, and can be personally used to develop insight into the notions of impermanence and the non-self derived from dhamma (Buddhist teachings). The video and photography documentations were edited and altered to generate a visual experience that echoes my thoughts and feelings developed during the proceedings; these moving images later inspired other series of hand-made artworks, including collages, drawings and paintings on paper and canvas, exhibited as part of the installations. Various techniques were applied so these objective components resonate a comparative experience of uncontrollability and controllability: dynamic and stillness, fast pace and slow rhythm, abstract and representation. Some two-dimensional pieces are transformed to three-dimensional and their displays keep changing from location to location, and from time to time, in conjunction with an unstable state of the mind. All artworks were created in various formats and interrelate and inform each other. They act together as evidence of the endless journey of artistic learning, which also mirrors the concept of self-learning in Buddhist meditation. </p

(De)contextualising Buddhist aesthetics

(De)contextualising Buddhist Aesthetics is a practice-led artistic research project focusing on the interchanging transition between Buddhist and artistic practices. Essentially inspired by the concept of vipassan&#257; meditation, I created a series of performances involving repetitive actions centring on the tasks of re-arranging readymade objects into multiple precarious configurations. Many exercises challenge the laws of gravity and other physical limitations of objects, as well as encouraging the learning experience through the process of trial and error. During the course of mindful observation of the performing body and objects, the mental state gradually gains moments of stillness and silence, which approach the meaning of emptiness (su&ntilde;&ntilde;at&#257;) in Buddhism. Repeated failures generate intermittent feelings of exhaustion and disappointment, which naturally become part of the progress, and can be personally used to develop insight into the notions of impermanence and the non-self derived from dhamma (Buddhist teachings). The video and photography documentations were edited and altered to generate a visual experience that echoes my thoughts and feelings developed during the proceedings; these moving images later inspired other series of hand-made artworks, including collages, drawings and paintings on paper and canvas, exhibited as part of the installations. Various techniques were applied so these objective components resonate a comparative experience of uncontrollability and controllability: dynamic and stillness, fast pace and slow rhythm, abstract and representation. Some two-dimensional pieces are transformed to three-dimensional and their displays keep changing from location to location, and from time to time, in conjunction with an unstable state of the mind. All artworks were created in various formats and interrelate and inform each other. They act together as evidence of the endless journey of artistic learning, which also mirrors the concept of self-learning in Buddhist meditation. </p

The High Costs of Low-Grade Inflammation: Persistent Fatigue as a Consequence of Reduced Cellular-Energy Availability and Non-adaptive Energy Expenditure

Chronic or persistent fatigue is a common, debilitating symptom of several diseases. Persistent fatigue has been associated with low-grade inflammation in several models of fatigue, including cancer-related fatigue and chronic fatigue syndrome. However, it is unclear how low-grade inflammation leads to the experience of fatigue. We here propose a model of an imbalance in energy availability and energy expenditure as a consequence of low-grade inflammation. In this narrative review, we discuss how chronic low-grade inflammation can lead to reduced cellular-energy availability. Low-grade inflammation induces a metabolic switch from energy-efficient oxidative phosphorylation to fast-acting, but less efficient, aerobic glycolytic energy production; increases reactive oxygen species; and reduces insulin sensitivity. These effects result in reduced glucose availability and, thereby, reduced cellular energy. In addition, emerging evidence suggests that chronic low-grade inflammation is associated with increased willingness to exert effort under specific circumstances. Circadian-rhythm changes and sleep disturbances might mediate the effects of inflammation on cellular-energy availability and non-adaptive energy expenditure. In the second part of the review, we present evidence for these metabolic pathways in models of persistent fatigue, focusing on chronic fatigue syndrome and cancer-related fatigue. Most evidence for reduced cellular-energy availability in relation to fatigue comes from studies on chronic fatigue syndrome. While the mechanistic evidence from the cancer-related fatigue literature is still limited, the sparse results point to reduced cellular-energy availability as well. There is also mounting evidence that behavioral-energy expenditure exceeds the reduced cellular-energy availability in patients with persistent fatigue. This suggests that an inability to adjust energy expenditure to available resources might be one mechanism underlying persistent fatigue

Disseminated Mycobacterium interjectum Infection with Bacteremia, Hepatic and Pulmonary Involvement Associated with a Long-Term Catheter Infection

We present a 49-year-old female with one year of intermittent fevers, chills, night sweats, and significant weight loss. Liver and lung biopsy showed evidence of a granulomatous process. Blood and liver biopsy cultures yielded growth of presumed Mycobacterium interjectum, thought to be related to a disseminated long-term central venous catheter infection. She successfully received one year of combined antimicrobial therapy after catheter removal without recurrence of disease. M. interjectum has been previously described as a cause of lymphadenitis in healthy children and associated with pulmonary disease in adults, although other localized infections have been reported. This is the first case described of a disseminated M. interjectum infection with bacteremia, hepatic and pulmonary involvement associated with a long-term catheter infection