Current dogma is that meaningful recovery of function after spinal cord injury (SCI) likely will require a combination of therapeutic interventions comprised of regenerative/neuroprotective transplants, addition of neurotrophic factors, elimination of inhibitory molecules, functional sensorimotor training, and/or stimulation of paralyzed muscles or spinal circuits. We routinely use: (1) peripheral nerve grafts to support and direct axonal regeneration across an incomplete cervical or a complete thoracic transection injury, (2) matrix modulation with chondroitinase (ChABC) to facilitate axonal extension beyond the distal graft-spinal cord interface and (3) exercise, such as forced wheel walking, bicycling or step training on a treadmill. We (and others) have demonstrated an increase in spinal cord levels of endogenous neurotrophic factors with exercise, which may be useful in facilitating elongation and/or synaptic activity of regenerating axons and plasticity of spinal neurons below the level of injury
rehabilitation; neurotrophic factors; neurotransplantation; cFos
Afferent feedback alters muscle activity during locomotion and must be tightly controlled. As primary afferent depolarization-induced presynaptic inhibition (PAD-PSI) regulates afferent signaling, we investigated hind limb PAD-PSI during locomotion in an in vitro rat spinal cord-hind limb preparation. We compared the relation of PAD-PSI, measured as dorsal root potentials (DRPs), to observed ipsilateral and contralateral limb endpoint forces. Afferents activated during stance-phase force strongly and proportionately influenced DRP magnitude in the swinging limb. Responses increased with locomotor frequency. Electrical stimulation of contralateral afferents also preferentially evoked DRPs in the opposite limb during swing (flexion). Nerve lesioning in conjunction with kinematic results support a prominent contribution from toe Golgi tendon organ afferents. Thus, force-dependent afferent feedback during stance binds interlimb sensorimotor state to a proportional PAD-PSI in the swinging limb, presumably to optimize interlimb coordination. These results complement known actions of ipsilateral afferents on PAD-PSI during locomotion.
presynaptic inhibition; primary afferent depolarization; dorsal root potential; primary afferent; Golgi tendon organ
A traumatic spinal injury can destroy cells, irreparably damage axons, and trigger a cascade of biochemical responses that increase the extent of injury. Although damaged central nervous system axons do not regrow well naturally, the distributed nature of the nervous system and its capacity to adapt provide opportunities for recovery of function. It is apparent that activity-dependent plasticity plays a role in this recovery and that the endogenous response to injury heightens the capacity for recovery for at least several weeks post-injury. To restore locomotor function, researchers have investigated the use of treadmill-based training, robots, and electrical stimulation to tap into adaptive activity-dependent processes. The current challenge is to maximize the degree of functional recovery. This manuscript reviews the endogenous neural system response to injury, and reviews data and presents novel analyses of these from a rat model of contusion injury that demonstrates how a targeted intervention can accelerate recovery, presumably by engaging processes that underlie activity-dependent plasticity.
spinal cord injury; locomotion; electrical stimulation; plasticity; kinematics; coordination
This narrative review examined randomized controlled trials of the management of obesity in primary care practice, in light of the Centers for Medicaid and Medicare Services’ (CMS) decision to support intensive behavioral weight loss counseling provided by physicians and related health professionals. Mean weight losses of 0.1–2.3 kg were observed with brief (10–15 minute) behavioral counseling delivered by primary care providers (PCPs) at monthly to quarterly visits. Losses increased to 1.7–7.5 kg when brief PCP counseling was combined with weight loss medication. Collaborative treatment, in which medical assistants delivered brief monthly behavioral counseling in conjunction with PCPs, produced losses of 1.6–4.6 kg in periods up to 2 years. Remotely-delivered, intensive (> monthly contact) behavioral counseling, as offered by telephone, yielded losses of 0.4–5.1 kg over the same period. Further study is needed of the frequency and duration of visits required to produce clinically meaningful weight loss (>5%) in primary care patients. In addition, trials are needed that examine the cost-effectiveness of PCP-delivered counseling, compared with that potentially provided by registered dietitians or well-studied commercial programs.
In type 1 diabetes (T1D) β-cell mass is markedly reduced by autoimmunity. Type 2 diabetes (T2D) results from inadequate β-cell mass and function that can no longer compensate for insulin resistance. The reduction of β-cell mass in T2D may result from increased cell death and/or inadequate birth through replication and neogenesis. Reduction in mass allows glucose levels to rise, which places β cells in an unfamiliar hyperglycemic environment, leading to marked changes in their phenotype and a dramatic loss of glucose-stimulated insulin secretion (GSIS), which worsens as glucose levels climb. Toxic effects of glucose on β cells (glucotoxicity) appear to be the culprit. This dysfunctional insulin secretion can be reversed when glucose levels are lowered by treatment, a finding with therapeutic significance. Restoration of β-cell mass in both types of diabetes could be accomplished by either β-cell regeneration or transplantation. Learning more about the relationships between β-cell mass, turnover, and function and finding ways to restore β-cell mass are among the most urgent priorities for diabetes research.
beta-cell; islets; diabetes; neogenesis; insulin secretion
The two types of adipose tissue in humans, white and brown, have distinct developmental origins and functions. Human white adipose tissue plays a pivotal role in maintaining whole body energy homeostasis by storing triglycerides when energy is in surplus, releasing free fatty acids as a fuel during energy shortage and secreting adipokines that are important for regulating lipid and glucose metabolism. The size of white adipose mass needs to be kept at a proper set point. Dramatic expansion of white fat mass causes obesity, which has now become a global epidemic disease, and increases the risk for the development of many life threatening diseases. Absence of white adipose tissue or abnormal white adipose tissue re-distribution leads to lipodystrophy, a condition often associated with metabolic disorders. Brown adipose tissue is a thermogenic organ, and its mass is inversely correlated with body mass index and age. Therapeutic approaches targeting adipose tissue have been proved to be effective in improving obesity-related metabolic disorders and promising new therapies could be developed in the near future.
WAT; BAT; obesity; lipodystrophy
Merkel cells are an enigmatic group of rare cells found in the skin of vertebrates. Most make contacts with somatosensory afferents to form Merkel cell-neurite complexes, which are gentle-touch receptors that initiate slowly adapting type I responses. The function of Merkel cells within the complex remains debated despite decades of research. Numerous anatomical studies demonstrate that Merkel cells form synaptic-like contacts with sensory afferent terminals. Moreover, recent molecular analysis reveals that Merkel cells express dozens of presynaptic molecules that are essential for synaptic vesicle release in neurons. Merkel cells also produce a host of neuro-active substances that can act as fast excitatory neurotransmitters or neuromodulators. Here, we review the major neurotransmitters found in Merkel cells and discuss these findings in relation to the potential function of Merkel cells in touch reception.
Merkel cell; touch; mechanotransduction; neurotransmitter; neuromodulator; somatosensory
Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the Western world and its incidence is increasing rapidly. NAFLD is a spectrum ranging from simple steatosis which is relatively benign hepatically to non-alcoholic steatohepatitis (NASH), which can progress to cirrhosis. Obesity, insulin resistance, type2 diabetes mellitus, and dyslipidemia are the most important risk factors for NAFLD. Due to heavy enrichment with metabolic risk factors, individuals with NAFLD are at significantly higher risk for cardiovascular disease. Individuals with NAFLD have higher incidence of type2 diabetes. The diagnosis of NAFLD requires imaging evidence of hepatic steatosis in the absence of competing etiologies including significant alcohol consumption. Liver biopsy remains the gold standard for diagnosing NASH and for determining prognosis. Weight loss remains a cornerstone of treatment. Weight loss of ~ 5% is believed to improve steatosis whereas ~10% weight loss is necessary to improve steatohepatitis. A number of pharmacologic therapies have been investigated to treat NASH, and agents such as vitamin E and thiazolidinediones have shown promise in select patient subgroups.
steatosis; steatohepatitis; fatty liver; thiazolidinediones
Modular pattern generator elements, also known as burst synergies or motor primitives, have become a useful and important way of describing motor behavior, albeit controversial. It is suggested that these synergy elements may comprise part of the pattern shaping layers of a McCrea/Rybak two layer pattern generator, as well as being used in other ways in spinal cord. The data supporting modular synergies ranges across species including man and encompasses motor pattern analyses and neural recordings. Recently, synergy persistence and changes following clinical trauma have been presented. These new data underscore the importance of understanding the modular structure of motor behaviors and the underlying circuitry in order to best provide principled therapies and to understand phenomena reported in the clinic. We discuss the evidence and different viewpoints on modularity, the neural underpinnings identified thus far, and possible critical issues for the future of this area.
motor primitives; synergies; modularity; spinal cord; pattern generation; stroke; spinal cord injury
Advances in molecular-genetic tools for labeling neuronal subtypes, and the emerging development of robust genetic probes for neural activity, are likely to revolutionize our understanding of the functional organization of neural circuits. In principle, these tools should be able to detect activity at cellular resolution for large ensembles of identified neuron types as they participate in specific behaviors. This review describes the use of genetically encoded calcium indicators (GECI's), combined with two-photon microscopy, to characterize V1 interneurons, known to be critical for setting the duration of the step cycle. All V1 interneurons arise from a common precursor population and express Engrailed-1 (En1). Our data show that although neighboring interneurons arising from the same developmental lineages often share features, such as projection patterns and neurotransmitter profiles, they are not irrevocably committed to have the same pattern of activity.
Engrailed-1; GCaMP3; two-photon
Neuromyelitis optica (NMO) is a debilitating autoimmune inflammatory disease of the central nervous system (CNS) that is distinct from multiple sclerosis (MS). The discovery of NMO-IgG in the serum of NMO, but not MS, patients was a breakthrough in defining diagnostic criteria for NMO. NMO-IgG is an antibody directed against the astrocytic water channel protein aquaporin-4 (AQP4). While there is evidence that NMO-IgG is also involved in mediating tissue damage in the CNS, many aspects of the pathogenic cascade in NMO remain to be determined. It is clear that antigen-specific T cells contribute to the generation of NMO-IgG in the peripheral immune compartment, as well as to the development of NMO lesions in the CNS. T helper 17 cells, equipped both in providing B cell help and inducing tissue inflammation, may be involved in NMO development and pathogenesis. Here, we review immunologic aspects of NMO, placing recent findings the biology of T–B cell cooperation in autoimmunity of the CNS into perspective.
neuromyelitis optica; inflammation; CNS
β-lactam antibiotics are the most commonly used antibacterial agents and growing resistance to these drugs is a concern. Metallo-β-lactamases are a diverse set of enzymes that catalyze the hydrolysis of a broad range of β-lactam drugs including carbapenems. This diversity is reflected in the observation that the enzyme mechanisms differ based on whether one or two zincs are bound in the active site which, in turn, is dependent on the subclass of β-lactamase. The dissemination of the genes encoding these enzymes among Gram-negative bacteria has made them an important cause of resistance. In addition, there are currently no clinically available inhibitors to block metallo-β-lactamase action. This review summarizes the numerous studies that have yielded insights into the structure, function, and mechanism of action of these enzymes.
β-lactamase; antibiotic resistance; carbapenem; zinc metallo-enzyme
The drugs of abuse, methamphetamine and MDMA, produce long-term decreases in markers of biogenic amine neurotransmission. These decreases have been traditionally linked to nerve terminals and are evident in a variety of species, including rodents, nonhuman primates, and humans. Recent studies indicate that the damage produced by these drugs may be more widespread than originally believed. Changes indicative of damage to cell bodies of biogenic and nonbiogenic amine–containing neurons in several brain areas and endothelial cells that make up the blood–brain barrier have been reported. The processes that mediate this damage involve not only oxidative stress but also include excitotoxic mechanisms, neuroinflammation, the ubiquitin proteasome system, as well as mitochondrial and neurotrophic factor dysfunction. These mechanisms also underlie the toxicity associated with chronic stress and human immunodeficiency virus (HIV) infection, both of which have been shown to augment the toxicity to methamphetamine. Overall, multiple mechanisms are involved and interact to promote neurotoxicity to methamphetamine and MDMA. Moreover, the high coincidence of substituted amphetamine abuse by humans with HIV and/or chronic stress exposure suggests a potential enhanced vulnerability of these individuals to the neurotoxic actions of the amphetamines.
amphetamine; methamphetamine; MDMA; neurotoxicity; apoptosis; excitotoxicity; neuroinflammation; proteasome; ubiquitination; neurodegeneration; drug abuse
The primate orbitofrontal cortex (OFC) is often treated as a single entity, but architectonic and connectional neuroanatomy indicates that it has distinguishable parts. Nevertheless, few studies have attempted to dissociate the functions of its subregions. Here we review findings from recent neuropsychological and neurophysiological studies that do so. The lateral OFC seems to be important for learning, representing and updating specific object–reward associations. Medial OFC seems to be important for value comparisons and choosing among objects on that basis. Rather than viewing this dissociation of function in terms of learning versus choosing, however, we suggest that it reflects the distinction between contrasts and comparisons: differences versus similarities. Making use of high-dimensional representations that arise from the convergence of several sensory modalities, the lateral OFC encodes contrasts among outcomes. The medial MFC reduces these contrasting representations of value to a single dimension, a common currency, in order to compare alternative choices.
Orbitofrontal cortex; macaque; reward; reversal learning
Cerebral ischemia, a focal or global insufficiency of blood flow to the brain, can arise through multiple mechanisms, including thrombosis and arterial hemorrhage. Ischemia is a major driver of stroke, one of the leading causes of morbidity and mortality worldwide. While the general etiology of cerebral ischemia and stroke has been known for some time, the conditions have only recently been considered treatable. This report describes current research in this field seeking to fully understand the pathomechanisms underlying stroke; to characterize the brain’s intrinsic injury, survival, and repair mechanisms; to identify putative drug targets as well as cell-based therapies; and to optimize the delivery of therapeutic agents to the damaged cerebral tissue.
stroke; cerebral ischemia; cerebrovascular disease; neurovascular unit; cell therapy; repair; immune response
The SH-2 containing inositol 5’ polyphosphatase 1 (SHIP1) is a multifunctional protein expressed predominantly, by hematopoietic cells. SHIP1 removes the 5’ phosphate from the product of PI3K, PI(3,4,5)P3, to generate PI(3,4)P2. Both PIP species influence the activity level of Akt, and ultimately regulate cell survival and differentiation. SHIP1 also harbors several protein interaction domains that endow it with many non-enzymatic cell signaling or receptor masking functions. In this review, we discuss the opposing roles of SHIP1 in cancer and in mucosal inflammation. On one hand, germline loss of SHIP1 causes myeloid lung consolidation and severe inflammation in the ileum, a phenotype that closely mimics human Crohn’s Disease and can be rescued by reconstitution with SHIP1 competent T cells. On the other, transient inhibition of the enzymatic activity of SHIP1 in cancer cell leads to apoptosis and enhances survival in lethal murine xenograft models. Overall, careful dissection of the different pathological mechanisms involved in several diseases provides novel opportunities for therapeutic intervention targeting SHIP1.
Inhibitors of the PI3K/mTOR signaling network are under development as novel cancer therapies. However, these compounds do not cause robust cytotoxic responses in tumor cells unless combined with other agents. Rational combinations with other targeted therapies will likely be necessary to achieve the potential of PI3K/mTOR inhibitors in oncology.
The bone marrow milieu comprised of both hematopoietic and non-hematopoietic lineages has a unique structural organization. Bone undergoes continuous remodeling in the body throughout life. This dynamic process involves a balance between bone-forming osteoblasts (OBs) derived from multipotent mesenchymal stem cells (MSCs) and bone-resorbing osteoclasts (OCs) derived from hematopoietic stem cells (HSCs). Src homology 2-domain-containing inositol 5′-phosphatase 1 (SHIP1) regulates cellular processes such as proliferation, differentiation, and survival via the PI3K/AKT signaling pathway initiated at the plasma membrane. SHIP1-deficient mice also exhibit profound osteoporosis that has been proposed to result from hyperresorptive activity by OCs. We have previously observed that SHIP1 is expressed in primary OBs, which display defective development in SHIP1-deficient mice. These findings led us to question whether SHIP1 plays a functional role in osteolineage development from MSC in vivo, which contributes to the osteoporotic phenotype in germline SHIP1 knockout mice. In this short review, we discuss our current understanding of inositol phospholipid signaling downstream of SHIP1 in bone biology.
SHIP1; bone; osteoclast; osteoblast; PI3K; inositol phospholipid
Patients with primary immunodeficiency (PID) provide rare opportunities to study the impact of specific gene mutations on the regulation of human B cell tolerance. Alterations in B cell receptor and Toll-like receptor signaling pathways result in a defective central checkpoint and a failure to counterselect developing autoreactive B cells in the bone marrow. In contrast, CD40L- and MHC class II–deficient patients only displayed peripheral B cell tolerance defects, suggesting that decreased numbers of regulatory T cells and increased concentration of B cell activating factor (BAFF) may interfere with the peripheral removal of autoreactive B cells. The pathways regulating B cell tolerance identified in PID patients are likely to be affected in patients with rheumatoid arthritis, systemic lupus erythematosus, and type 1 diabetes who display defective central and peripheral B cell tolerance checkpoints. Indeed, risk alleles encoding variants altering BCR signaling, such as PTPN22 alleles associated with the development of these diseases, interfere with the removal of developing autoreactive B cells. Hence, insights into B cell selection from PID patients are highly relevant to the understanding of the etiology of autoimmune conditions.
B cell tolerance; B cell receptor; Toll-like receptors; receptor editing
Genome wide association (GWA) can elucidate molecular genetic bases for human individual differences in “complex” phenotypes that include vulnerability to addiction. Here, we review: a) evidence that supports polygenic models with (at least) modest heterogeneity for the genetic architectures of addiction and several related phenotypes; b) technical and ethical aspects of importance for understanding genome wide association data: genotyping in individual samples vs DNA pools, analytic approaches, power estimation and ethical issues in genotyping individuals with illegal behaviors; c) the samples and the data that shape our current understanding of the molecular genetics of individual differences in vulnerability to substance dependence and related phenotypes; d) overlaps between GWA datasets for dependence on different substances; e) overlaps between GWA data for addictions vs other heritable, brain-based phenotypes that include: i) bipolar disorder, ii) cognitive ability, iii) frontal lobe brain volume, iv) ability to successfully quit smoking, v) neuroticism and vi) Alzheimer’s disease. These convergent results identify potential targets for drugs that might modify addictions and play roles in these other phenotypes. They add to evidence that individual differences in the quality and quantity of brain connections make pleiotropic contributions to individual differences in vulnerability to addictions and to related brain disorders and phenotypes. A “connectivity constellation” of brain phenotypes and disorders appears to receive substantial pathogenic contributions from individual differences in a constellation of genes whose variants provide individual differences in the specification of brain connectivities during development and in adulthood. Heritable brain differences that underlie addiction vulnerability thus lie squarely in the midst of the repertoire of heritable brain differences that underlie vulnerability to other common brain disorders and phenotypes.
pleiotropic; cell adhesion; monte carlo
Major depression and addiction are mental health problems associated with stressful events in life with high relapse and reoccurrence even after treatment. Many laboratories were not able to detect the presence of CB2 cannabinoid receptors (CB2-Rs) in healthy brains, but there has been demonstration of CB2-R expression in rat microglial cells and other brain associated cells during inflammation. Therefore, neuronal expression of CB2-Rs had been ambiguous and controversial and its role in depression and substance abuse is unknown. In this study we tested the hypothesis that genetic variants of CB2 gene might be associated with depression in a human population and that alteration in CB2 gene expression may be involved in the effects of abused substances including opiates, cocaine and ethanol in rodents. Here we demonstrate that a high incidence of (Q63R) but not (H316Y) polymorphism in the CB2 gene was found in Japanese depressed subjects. CB2-Rs and their gene transcripts are expressed in the brains of naïve mice and are modulated following exposure to stressors and administration of abused drugs. Mice that developed alcohol preference had reduced CB2 gene expression and chronic treatment with JWH015 a putative CB2-R agonist, enhanced alcohol consumption in stressed but not in control mice. The direct intracerebroventricular microinjection of CB2 anti-sense oligonucleotide into the mouse brain reduced mouse aversions in the plus-maze test, indicating the functional presence of CB2-Rs in the brain that modifies behavior. Using electron microscopy we report the sub cellular localization of CB2-Rs that are mainly on post-synaptic elements in rodent brain. Our data demonstrate the functional expression of CB2-Rs in brain that may provide novel targets for the effects of cannabinoids in depression and substance abuse disorders beyond neuro-immunocannabinoid activity.
Neuronal CB2 Cannabinoid Receptors; Brain; electron micrograph; chronic mild stress; anhedonia; depression; drug abuse
Antimuscle specific kinase (anti-MuSK) myasthenia (AMM) differs from antiacetylcholine receptor myasthenia gravis in exhibiting more focal muscle involvement (neck, shoulder, facial, and bulbar muscles) with wasting of the involved, primarily axial, muscles. AMM is not associated with thymic hyperplasia and responds poorly to anticholinesterase treatment. Animal models of AMM have been induced in rabbits, mice, and rats by immunization with purified xenogeneic MuSK ectodomain, and by passive transfer of large quantities of purified serum IgG from AMM patients into mice. The models have confirmed the pathogenic role of the MuSK antibodies in AMM and have demonstrated the involvement of both the presynaptic and postsynaptic components of the neuromuscular junction. The observations in this human disease and its animal models demonstrate the role of MuSK not only in the formation of this synapse but also in its maintenance.
animal models; autoimmune; muscle-specific kinase; muscle wasting; MuSK; myasthenia; neuromuscular junction; synapse
Inducing expression of endogenous fetal globin (γ-globin) gene expression to 60-70% of alpha globin synthesis produces β-thalassemia trait globin synthetic ratios and can reduce anemia to a mild level. Several classes of therapeutics have induced γ-globin expression in beta thalassemia patients and subsequently raised total hemoglobin levels, demonstrating proof-of-concept of the approach. Butyrate treatment eliminated transfusion requirements in formerly transfusion-dependent patients with treatment for as long as 7 years. However, prior generations were not readily applicable for widespread use. Currently, a novel oral dual-action therapeutic sodium 2,2-dimethylbutyrate is in clinical trials, an oral decitabine formulation is under development, and agents with complementary mechanisms of action can be applied in combined regimens. Identification of 3 major genetic trait loci which modulate clinical severity provides avenues for developing tailored regimens. These refinements offer renewed potential to apply fetal globin induction as a treatment approach in patient-friendly regimens that can be used world-wide.
thalassemia; short chain fatty acids; butyrates; erythropoiesis; fetal globin; quantitative trait loci
The ability to inhibit expression of a mutant allele while retaining expression of wild-type protein might provide a useful approach to treating Huntington’s Disease (HD) and other inherited pathologies. The mutant form of huntingtin (HTT), the protein responsible for HD, is encoded by an mRNA containing an expanded CAG repeat. We demonstrate that peptide nucleic acid (PNA) conjugates and locked nucleic acids (LNAs) complementary to the CAG repeat selectively block expression of mutant HTT. The selectivity of inhibition is at least as good as that shown by an siRNA targeted to a deletion polymorphism. Our data suggest that antisense oligomers are promising subject for further development as an anti-HD therapeutic strategy.
Huntington’s disease; huntingtin; allele selectivity; peptide nucleic acid; PNA; locked nucleic acid; LNA; siRNA; trinucleotide repeat; CAG repeat
Siglecs are cell-surface proteins found primarily on hematopoietic cells. By definition, they are members of the immunoglobulin gene super-family and bind sialic acid. Most contain cytoplasmic tyrosine motifs implicated in cell signaling. This review will first summarize characteristics common and unique to Siglecs, followed by a discussion of each human Siglec in numerical order, mentioning in turn its closest murine ortholog or paralog. Each section will describe its pattern of cellular expression, latest known immune functions, ligands, and signaling pathways, with the focus being predominantly on CD33-related Siglecs. Potential clinical and therapeutic implications of each Siglec will also be covered.
Siglec; human; mouse; leukocyte; ITIM; ITAM; sialic acid; lectin