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Therapeutic neuroscience

Davide Amato, Clare L Beasley, Margaret K Hahn, Anthony C Vernon
Antipsychotic drugs, all of which block the dopamine D2 receptor to a greater or lesser extent, are the mainstay for the pharmacological treatment of schizophrenia. Engaging in a deeper understanding of how antipsychotics act on the brain and body, at the cellular, molecular and physiological level is vital to comprehend both the beneficial and potentially harmful actions of these medications and stimulate development of novel therapeutics. To address this, we review recent advances in our understanding of neuroadaptations to antipsychotics, focusing on (1) treatment efficacy, (2) impact on brain volume and (3) evidence from human post-mortem studies that attempt to dissect neuropathological effects of antipsychotic drugs from organic schizophrenia neurobiology and (4) cardio-metabolic side effects...
October 15, 2016: Neuroscience and Biobehavioral Reviews
Tyler A Johnson, Laura Milan-Lobo, Tao Che, Madeline Ferwerda, Eptisam Lambo, Nicole L McIntosh, Fei Li, Li He, Nicholas Lorig-Roach, Phillip Crews, Jennifer Lynne Whistler
Opioid therapeutics are excellent analgesics, whose utility is compromised by dependence. Morphine (1) and its clinically relevant derivatives such as OxyContin® (4), Vicodin® (5) and Dilaudid® (6) are "biased" agonists at the µ opioid receptor (OR), wherein they engage G-protein signaling but poorly engage β-arrestin and the endocytic machinery. In contrast, the endorphins, met-enkephalin (14) and β-endorphin (15), endogenous peptide agonists for ORs, are more potent analgesics then 1, show reduced liability for tolerance and dependence, and engage both G-protein and β-arrestin pathways as "balanced" agonists...
October 17, 2016: ACS Chemical Neuroscience
E Carlino, A Piedimonte, F Benedetti
Placebos have long been considered a nuisance in clinical research, for they have always been used as comparators for the validation of new treatments. By contrast, today they represent an active field of research, and, due to the involvement of many mechanisms, the study of the placebo effect can actually be viewed as a melting pot of concepts and ideas for neuroscience. There is not a single placebo effect, but many, with different mechanisms across different medical conditions and therapeutic interventions...
2017: Handbook of Clinical Neurology
Adi Pinkas, Michael Aschner
Advanced glycation end-products (AGEs) are non-enzymatically glycated proteins, lipids and nucleic acids. These compounds both originate exogenously and are formed endogenously, and are associated, along with one of their receptors - RAGE, with a variety of pathologies and neurodegeneration. Some of their deleterious effects include affecting insulin signaling and FOXO-related pathways in both receptor-dependent and -independent manner. A potential ameliorating agent for these effects is insulin, which is being studied in several in vivo and in vitro models; one of these models is C...
October 5, 2016: Chemical Research in Toxicology
Michelle G Craske, Alicia E Meuret, Thomas Ritz, Michael Treanor, Halina J Dour
Anhedonia, or loss of interest or pleasure in usual activities, is characteristic of depression, some types of anxiety, as well as substance abuse and schizophrenia. Anhedonia is a predictor of poor long-term outcomes, including suicide, and poor treatment response. Because extant psychological and pharmacological treatments are relatively ineffective for anhedonia, there is an unmet therapeutic need for this high-risk symptom. Current psychological and drug treatments for anxiety and depression focus largely on reducing excesses in negative affect rather than improving deficits in positive affect...
October 2016: Depression and Anxiety
David A Martin, Charles D Nichols
There has recently been a resurgence of interest in psychedelics, substances that profoundly alter perception and cognition and have recently demonstrated therapeutic efficacy to treat anxiety, depression, and addiction in the clinic. The receptor mechanisms that drive their molecular and behavioral effects involve activation of cortical serotonin 5-HT2A receptors, but the responses of specific cellular populations remain unknown. Here, we provide evidence that a small subset of 5-HT2A-expressing excitatory neurons is directly activated by psychedelics and subsequently recruits other select cell types including subpopulations of inhibitory somatostatin and parvalbumin GABAergic interneurons, as well as astrocytes, to produce distinct and regional responses...
September 2016: EBioMedicine
Gregory B Potter, Magdalena A Petryniak
Neuroinflammation, activation of innate immune components of the nervous system followed by an adaptive immune response, is observed in most leukodystrophies and coincides with white matter pathology, disease progression, and morbidity. Despite this, there is a major gap in our knowledge of the contribution of the immune system to disease phenotype. Inflammation in Krabbe's disease has been considered a secondary effect, resulting from cell-autonomous oligodendroglial cell death or myelin loss resulting from psychosine accumulation...
November 2016: Journal of Neuroscience Research
Samantha J Spratley, Janet E Deane
Missense mutations in the lysosomal hydrolase β-galactocerebrosidase (GALC) account for at least 40% of known cases of Krabbe disease (KD). Most of these missense mutations are predicted to disrupt the fold of the enzyme, preventing GALC in sufficient amounts from reaching its site of action in the lysosome. The predominant central nervous system (CNS) pathology and the absence of accumulated primary substrate within the lysosome mean that strategies used to treat other lysosomal storage disorders (LSDs) are insufficient in KD, highlighting the still unmet clinical requirement for successful KD therapeutics...
November 2016: Journal of Neuroscience Research
Peirong Hu, Yedda Li, Nana Nikolaishvili-Feinberg, Giuseppe Scesa, Yanmin Bi, Dao Pan, Dominic Moore, Ernesto R Bongarzone, Mark S Sands, Ryan Miller, Tal Kafri
Currently, presymtomatic hematopoietic stem and progenitor cell transplantation (HSPCT) is the only therapeutic modality that alleviates Krabbe's disease (KD)-induced central nervous system damage. However, all HSPCT-treated patients exhibit severe deterioration in peripheral nervous system function characterized by major motor and expressive language pathologies. We hypothesize that a combination of several mechanisms contribute to this phenomenon, including 1) nonoptimal conditioning protocols with consequent inefficient engraftment and biodistribution of donor-derived cells and 2) insufficient uptake of donor cell-secreted galactocerebrosidease (GALC) secondary to a naturally low expression level of the cation-independent mannose 6-phosphate-receptor (CI-MPR)...
November 2016: Journal of Neuroscience Research
Ying Deng-Bryant, Lai Yee Leung, Krista Caudle, Frank Tortella, Deborah Shear
The Morris water maze (MWM) task is one of the most widely used and versatile tools in behavioral neuroscience for evaluating spatial learning and memory. With regard to detecting cognitive deficits following central nervous system (CNS) injuries, MWM has been commonly utilized in various animal models of neurotrauma, such as fluid percussion injury (FPI), cortical controlled impact (CCI) injury, weight-drop impact injury, and penetrating ballistic-like brain injury (PBBI). More importantly, it serves as a therapeutic index for assessing the efficacy of treatment interventions on cognitive performance following neurotrauma...
2016: Methods in Molecular Biology
Susan Bell
Idiopathic intracranial hypertension has been recognized in the literature for over 100 years. It is a disease of elevated intracranial pressure without evidence of a space-occupying lesion found most often in obese women of childbearing age. The signs and symptoms have been well described; however, the etiology is yet unknown. Medical and surgical treatment is aimed at the preservation of vision and improvement in symptoms. The medical literature is replete with articles addressing the epidemiology, pathophysiology, clinical and imaging features, and treatment...
September 5, 2016: Journal of Neuroscience Nursing: Journal of the American Association of Neuroscience Nurses
Nancy Lee, Carolyn R Serbinski, Makayla R Braunlin, Matthew S Rasch, Carolyn E Rydyznski, A John MacLennan
The molecular mechanisms maintaining adult motor innervation are comparatively unexplored relative to those involved during development. In addition to the fundamental neuroscience question, this area has important clinical ramifications given that loss of neuromuscular contact is thought to underlie several adult onset human neuromuscular diseases including amyotrophic lateral sclerosis. Indirect evidence suggest that ciliary neurotrophic factor (CNTF) receptors may contribute to adult motor neuron axon maintenance...
September 7, 2016: European Journal of Neuroscience
Joyce Keifer, Cliff H Summers
Current trends in neuroscience research have moved toward a reliance on rodent animal models to study most aspects of brain function. Such laboratory-reared animals are highly inbred, have been disengaged from their natural environments for generations and appear to be of limited predictive value for successful clinical outcomes. In this Perspective article, we argue that research on a rich diversity of animal model systems is fundamental to new discoveries in evolutionarily conserved core physiological and molecular mechanisms that are the foundation of human brain function...
2016: Frontiers in Systems Neuroscience
Yazan Haddad, Zbynek Heger, Vojtech Adam
The human dopamine, norepinephrine and serotonin transporters (hDAT, hNET and hSERT) are carriers of neurotransmitters and targets for many drugs. Pioneering works in the past three years to elucidate experimental models of the drosophila dDAT and human hSERT structures will rapidly impact the field of neuroscience. Here, we evaluated automated homology-based human models of these transporters, employing systematic physics-based, knowledge-based and empirical-based check. Modeling guidelines were conveyed with attention to the central binding site (S1), secondary binding site (S2), and the extracellular loops EL2 and EL4...
September 6, 2016: ACS Chemical Neuroscience
Claudia Subic-Wrana, Leslie S Greenberg, Richard D Lane, Matthias Michal, Jörg Wiltink, Manfred E Beutel
OBJECTIVES: Affective change has been considered the hallmark of therapeutic change in psychoanalysis. Psychoanalytic writers have begun to incorporate theoretically the advanced understanding of emotional processing and transformation of the affective neurosciences. We ask if this theoretical advancement is reflected in treatment techniques addressing the processing of emotion. METHODS: We review psychoanalytic models and treatment recommendations of maladaptive affect processing in the light of a neuroscientifically informed model of achieving psychotherapeutic change by activation and reconsolidation of emotional memory...
September 2016: Zeitschrift Für Psychosomatische Medizin und Psychotherapie
Laura Fernández-García, Núria Marí-Buyé, Juan A Barios, Rodrigo Madurga, Manuel Elices, José Pérez-Rigueiro, Milagros Ramos, Gustavo V Guinea, Daniel González-Nieto
: At present, effective therapies to repair the central nervous system do not exist. Biomaterials might represent a new frontier for the development of neurorestorative therapies after brain injury and degeneration. In this study, an in situ gelling silk fibroin hydrogel was developed via the sonication-induced gelation of regenerated silk fibroin solutions. An adequate timeframe for the integration of the biomaterial into the brain tissue was obtained by controlling the intensity and time of sonication...
November 2016: Acta Biomaterialia
C J Westmark, D K Sokol, B Maloney, D K Lahiri
Fragile X syndrome (FXS) is the most common form of inherited intellectual disability and is associated with up to 5% of autism cases. Several promising drugs are in preclinical testing for FXS; however, bench-to-bedside plans for the clinic are severely limited due to lack of validated biomarkers and outcome measures. Published work from our laboratories has demonstrated altered levels of amyloid-beta (Aβ) precursor protein (APP) and its metabolites in FXS and idiopathic autism. Westmark and colleagues have focused on β-secretase (amyloidogenic) processing and the accumulation of Aβ peptides in adult FXS models, whereas Lahiri and Sokol have studied α-secretase (non-amyloidogenic or anabolic) processing and altered levels of sAPPα and Aβ in pediatric autism and FXS...
October 2016: Molecular Psychiatry
Colin Reardon
Communication between the nervous and immune systems can significantly alter immune cell function in a number of inflammatory diseases. Elegant studies have defined a basic functional circuit in a "cholinergic anti-inflammatory pathway" that highlights a unique role for the vagus nerve, and has brought about a resurgence in the field of neuro-immunology. This research has further identified that in addition to tonic signals that can restrain immune cell activation; the anti-inflammatory reflex arc is amiable to targeted stimulation as a therapeutic modality...
October 2016: Immunology Letters
Ryan Smith, Richard D Lane
While psychiatry and clinical psychology have long discussed the topic of unconscious emotion, and its potentially explanatory role in psychopathology, this topic has only recently begun to receive attention within cognitive neuroscience. In contrast, neuroscientific research on conscious vs. unconscious processes within perception, memory, decision-making, and cognitive control has seen considerable advances in the last two decades. In this article, we extrapolate from this work, as well as from recent neural models of emotion processing, to outline multiple plausible neuro-cognitive mechanisms that may be able to explain why various aspects of one's own emotional reactions can remain unconscious in specific circumstances...
October 2016: Neuroscience and Biobehavioral Reviews
Himanshu Sekhar Behera, Gita Satpathy, Manjari Tripathi
BACKGROUND: Acanthamoeba spp. are free-living ubiquitous protozoans capable of causing Acanthamoeba meningitis/meningoencephalitis (AME) of the central nervous system in humans. Acanthamoeba spp. are divided into 20 different genotypes (T1-T20) on the basis of variation in nucleotide sequences of the 18S rRNA gene. The objective of this study was to identify the genotypes of Acanthamoeba spp. in patients of Acanthamoeba meningitis/meningoencephalitis (AME) using 18S rRNA gene-based PCR assay...
2016: Parasites & Vectors
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