The human genome encodes a vast repertoire of protein non-coding RNAs (ncRNA), some specific to the brain. MicroRNAs, which interfere with the translation of target mRNAs, are of particular interest ...since their deregulation has been implicated in neurodegenerative disorders like Alzheimer's disease (AD). However, it remains challenging to link the complex body of observations on miRNAs and AD into a coherent framework. Using extensive graphical support, this article discusses how a diverse panoply of miRNAs convergently and divergently impact (and are impacted by) core pathophysiological processes underlying AD: neuroinflammation and oxidative stress; aberrant generation of β-amyloid-42 (Aβ42); anomalies in the production, cleavage and post-translational marking of Tau; impaired clearance of Aβ42 and Tau; perturbation of axonal organisation; disruption of synaptic plasticity; endoplasmic reticulum stress and the unfolded protein response; mitochondrial dysfunction; aberrant induction of cell cycle re-entry; and apoptotic loss of neurons. Intriguingly, some classes of miRNA provoke these cellular anomalies, whereas others act in a counter-regulatory, protective mode. Moreover, changes in levels of certain species of miRNA are a consequence of the above-mentioned anomalies. In addition to miRNAs, circular RNAs, piRNAs, long non-coding RNAs and other types of ncRNA are being increasingly implicated in AD. Overall, a complex mesh of deregulated and multi-tasking ncRNAs reciprocally interacts with core pathophysiological mechanisms underlying AD. Alterations in ncRNAs can be detected in CSF and the circulation as well as the brain and are showing promise as biomarkers, with the ultimate goal clinical exploitation as targets for novel modes of symptomatic and course-altering therapy.
Neurodevelopmental disorders (NDDs) are characterized by aberrant and delayed early-life development of the brain, leading to deficits in language, cognition, motor behaviour and other functional ...domains, often accompanied by somatic symptoms. Environmental factors like perinatal infection, malnutrition and trauma can increase the risk of the heterogeneous, multifactorial and polygenic disorders, autism and schizophrenia. Conversely, discrete genetic anomalies are involved in Down, Rett and Fragile X syndromes, tuberous sclerosis and neurofibromatosis, the less familiar Phelan–McDermid, Sotos, Kleefstra, Coffin–Lowry and “ATRX” syndromes, and the disorders of imprinting, Angelman and Prader–Willi syndromes. NDDs have been termed “synaptopathies” in reference to structural and functional disturbance of synaptic plasticity, several involve abnormal Ras-Kinase signalling (“rasopathies”), and many are characterized by disrupted cerebral connectivity and an imbalance between excitatory and inhibitory transmission. However, at a different level of integration, NDDs are accompanied by aberrant “epigenetic” regulation of processes critical for normal and orderly development of the brain. Epigenetics refers to potentially-heritable (by mitosis and/or meiosis) mechanisms controlling gene expression without changes in DNA sequence. In certain NDDs, prototypical epigenetic processes of DNA methylation and covalent histone marking are impacted. Conversely, others involve anomalies in chromatin-modelling, mRNA splicing/editing, mRNA translation, ribosome biogenesis and/or the regulatory actions of small nucleolar RNAs and micro-RNAs. Since epigenetic mechanisms are modifiable, this raises the hope of novel therapy, though questions remain concerning efficacy and safety. The above issues are critically surveyed in this review, which advocates a broad-based epigenetic framework for understanding and ultimately treating a diverse assemblage of NDDs (“epigenopathies”) lying at the interface of genetic, developmental and environmental processes.
This article is part of the Special Issue entitled ‘Neurodevelopmental Disorders’.
► Neurodevelopmental disorders like autism involve abnormal development of brain. ► Some rare disorders are monogenetic, like Fragile X, but most are polygenetic. ► Certain involve environmental factors, like pre-natal infection or early life trauma. ► Both genetic and environmental factors disrupt epigenetic control of gene expression. ► Processes include DNA and histone methylation, and miRNA control of mRNA translation.
Major depression is a debilitating and recurrent disorder with a substantial lifetime risk and a high social cost. Depressed patients generally display co-morbid symptoms, and depression frequently ...accompanies other serious disorders. Currently available drugs display limited efficacy and a pronounced delay to onset of action, and all provoke distressing side effects. Cloning of the human genome has fuelled expectations that symptomatic treatment may soon become more rapid and effective, and that depressive states may ultimately be "prevented" or "cured". In pursuing these objectives, in particular for genome-derived, non-monoaminergic targets, "specificity" of drug actions is often emphasized. That is, priority is afforded to agents that interact exclusively with a single site hypothesized as critically involved in the pathogenesis and/or control of depression. Certain highly selective drugs may prove effective, and they remain indispensable in the experimental (and clinical) evaluation of the significance of novel mechanisms. However, by analogy to other multifactorial disorders, "multi-target" agents may be better adapted to the improved treatment of depressive states. Support for this contention is garnered from a broad palette of observations, ranging from mechanisms of action of adjunctive drug combinations and electroconvulsive therapy to "network theory" analysis of the etiology and management of depressive states. The review also outlines opportunities to be exploited, and challenges to be addressed, in the discovery and characterization of drugs recognizing multiple targets. Finally, a diversity of multi-target strategies is proposed for the more efficacious and rapid control of core and co-morbid symptoms of depression, together with improved tolerance relative to currently available agents.
Fear is an adaptive component of the acute "stress" response to potentially-dangerous (external and internal) stimuli which threaten to perturb homeostasis. However, when disproportional in ...intensity, chronic and/or irreversible, or not associated with any genuine risk, it may be symptomatic of a debilitating anxious state: for example, social phobia, panic attacks or generalized anxiety disorder. In view of the importance of guaranteeing an appropriate emotional response to aversive events, it is not surprising that a diversity of mechanisms are involved in the induction and inhibition of anxious states. Apart from conventional neurotransmitters, such as monoamines, gamma-amino-butyric acid (GABA) and glutamate, many other modulators have been implicated, including: adenosine, cannabinoids, numerous neuropeptides, hormones, neurotrophins, cytokines and several cellular mediators. Accordingly, though benzodiazepines (which reinforce transmission at GABA(A) receptors), serotonin (5-HT)(1A) receptor agonists and 5-HT reuptake inhibitors are currently the principle drugs employed in the management of anxiety disorders, there is considerable scope for the development of alternative therapies. In addition to cellular, anatomical and neurochemical strategies, behavioral models are indispensable for the characterization of anxious states and their modulation. Amongst diverse paradigms, conflict procedures--in which subjects experience opposing impulses of desire and fear--are of especial conceptual and therapeutic pertinence. For example, in the Vogel Conflict Test (VCT), the ability of drugs to release punishment-suppressed drinking behavior is evaluated. In reviewing the neurobiology of anxious states, the present article focuses in particular upon: the multifarious and complex roles of individual modulators, often as a function of the specific receptor type and neuronal substrate involved in their actions; novel targets for the management of anxiety disorders; the influence of neurotransmitters and other agents upon performance in the VCT; data acquired from complementary pharmacological and genetic strategies and, finally, several open questions likely to orientate future experimental- and clinical-research. In view of the recent proliferation of mechanisms implicated in the pathogenesis, modulation and, potentially, treatment of anxiety disorders, this is an opportune moment to survey their functional and pathophysiological significance, and to assess their influence upon performance in the VCT and other models of potential anxiolytic properties.
Though a multi-facetted disorder, Parkinson's disease is prototypically characterized by neurodegeneration of nigrostriatal dopaminergic neurons of the substantia nigra pars compacta, leading to a ...severe disruption of motor function. Accordingly, L-DOPA, the metabolic precursor of dopamine (DA), is well-established as a treatment for the motor deficits of Parkinson's disease despite long-term complications such as dyskinesia and psychiatric side-effects. Paradoxically, however, despite the traditional assumption that L-DOPA is transformed in residual striatal dopaminergic neurons into DA, the mechanism of action of L-DOPA is neither simple nor entirely clear. Herein, focussing on its influence upon extracellular DA and other neuromodulators in intact animals and experimental models of Parkinson's disease, we highlight effects other than striatal generation of DA in the functional profile of L-DOPA. While not excluding a minor role for glial cells, L-DOPA is principally transformed into DA in neurons yet, interestingly, with a more important role for serotonergic than dopaminergic projections. Moreover, in addition to the striatum, L-DOPA evokes marked increases in extracellular DA in frontal cortex, nucleus accumbens, the subthalamic nucleus and additional extra-striatal regions. In considering its functional profile, it is also important to bear in mind the marked (probably indirect) influence of L-DOPA upon cholinergic, GABAergic and glutamatergic neurons in the basal ganglia and/or cortex, while anomalous serotonergic transmission is incriminated in the emergence of L-DOPA elicited dyskinesia and psychosis. Finally, L-DOPA may exert intrinsic receptor-mediated actions independently of DA neurotransmission and can be processed into bioactive metabolites. In conclusion, L-DOPA exerts a surprisingly complex pattern of neurochemical effects of much greater scope that mere striatal transformation into DA in spared dopaminergic neurons. Their further experimental and clinical clarification should help improve both L-DOPA-based and novel strategies for controlling the motor and other symptoms of Parkinson's disease.
•Social cognition, the guiding of behaviour by social cues, is disrupted in schizophrenia.•No specific treatments are available, and improved animal models are needed for their discovery.•A meeting ...was coordinated by the NIMH-funded “CNTRICS” group to discuss improved procedures.•Two were selected: social recognition/preference in rodents and gaze-following in non-human primates.•Both these and complementary models require further development and better translation into humans.
Social cognition refers to processes used to monitor and interpret social signals from others, to decipher their state of mind, emotional status and intentions, and select appropriate social behaviour. Social cognition is sophisticated in humans, being embedded with verbal language and enacted in a complex cultural environment. Its disruption characterises the entire course of schizophrenia and is correlated with poor functional outcome. Further, deficits in social cognition are related to impairment in other cognitive domains, positive symptoms (paranoia and delusions) and negative symptoms (social withdrawal and reduced motivation). In light of the significance and inadequate management of social cognition deficits, there is a need for translatable experimental procedures for their study, and identification of effective pharmacotherapy. No single paradigm captures the multi-dimensional nature of social cognition, and procedures for assessing ability to infer mental states are not well-developed for experimental therapeutic settings. Accordingly, a recent CNTRICS meeting prioritised procedures for measuring a specific construct: “acquisition and recognition of affective (emotional) states”, coupled to individual recognition. Two complementary paradigms for refinement were identified: social recognition/preference in rodents, and visual tracking of social scenes in non-human primates (NHPs). Social recognition is disrupted in genetic, developmental or pharmacological disease models for schizophrenia, and performance in both procedures is improved by the neuropeptide oxytocin. The present article surveys a broad range of procedures for studying social cognition in rodents and NHPs, discusses advantages and drawbacks, and focuses on development of social recognition/preference and gaze-following paradigms for improved study of social cognition deficits in schizophrenia and their potential treatment.
Studies of psychiatric disorders have traditionally focused on emotional symptoms such as depression, anxiety and hallucinations. However, poorly controlled cognitive deficits are equally prominent ...and severely compromise quality of life, including social and professional integration. Consequently, intensive efforts are being made to characterize the cellular and cerebral circuits underpinning cognitive function, define the nature and causes of cognitive impairment in psychiatric disorders and identify more effective treatments. Successful development will depend on rigorous validation in animal models as well as in patients, including measures of real-world cognitive functioning. This article critically discusses these issues, highlighting the challenges and opportunities for improving cognition in individuals suffering from psychiatric disorders.
Descending control of pain Millan, Mark J
Progress in neurobiology,
04/2002, Letnik:
66, Številka:
6
Journal Article
Recenzirano
Upon receipt in the dorsal horn (DH) of the spinal cord, nociceptive (pain-signalling) information from the viscera, skin and other organs is subject to extensive processing by a diversity of ...mechanisms, certain of which enhance, and certain of which inhibit, its transfer to higher centres. In this regard, a network of descending pathways projecting from cerebral structures to the DH plays a complex and crucial role. Specific centrifugal pathways either suppress (descending inhibition) or potentiate (descending facilitation) passage of nociceptive messages to the brain. Engagement of descending inhibition by the opioid analgesic, morphine, fulfils an important role in its pain-relieving properties, while induction of analgesia by the adrenergic agonist, clonidine, reflects actions at alpha(2)-adrenoceptors (alpha(2)-ARs) in the DH normally recruited by descending pathways. However, opioids and adrenergic agents exploit but a tiny fraction of the vast panoply of mechanisms now known to be involved in the induction and/or expression of descending controls. For example, no drug interfering with descending facilitation is currently available for clinical use. The present review focuses on: (1) the organisation of descending pathways and their pathophysiological significance; (2) the role of individual transmitters and specific receptor types in the modulation and expression of mechanisms of descending inhibition and facilitation and (3) the advantages and limitations of established and innovative analgesic strategies which act by manipulation of descending controls. Knowledge of descending pathways has increased exponentially in recent years, so this is an opportune moment to survey their operation and therapeutic relevance to the improved management of pain.
Abstract Schizophrenia is a complex and multifactorial disorder generally diagnosed in young adults at the time of the first psychotic episode of delusions and hallucinations. These positive symptoms ...can be controlled in most patients by currently-available antipsychotics. Conversely, they are poorly effective against concomitant neurocognitive dysfunction, deficits in social cognition and negative symptoms (NS), which strongly contribute to poor functional outcome. The precise notion of NS has evolved over the past century, with recent studies – underpinned by novel rating methods – suggesting two major sub-domains: “decreased emotional expression”, incorporating blunted affect and poverty of speech, and “avolition”, which embraces amotivation, asociality and “anhedonia” (inability to anticipate pleasure). Recent studies implicate a dysfunction of frontocortico-temporal networks in the aetiology of NS, together with a disruption of cortico-striatal circuits, though other structures are also involved, like the insular and parietal cortices, amygdala and thalamus. At the cellular level, a disruption of GABAergic–glutamatergic balance, dopaminergic signalling and, possibly, oxytocinergic and cannibinoidergic transmission may be involved. Several agents are currently under clinical investigation for the potentially improved control of NS, including oxytocin itself, N-Methyl- d -Aspartate receptor modulators and minocycline. Further, magnetic-electrical “stimulation” strategies to recruit cortical circuits and “cognitive–behavioural–psychosocial” therapies likewise hold promise. To acquire novel insights into the causes and treatment of NS, experimental study is crucial, and opportunities are emerging for improved genetic, pharmacological and developmental modelling, together with more refined readouts related to deficits in reward, sociality and “expression”. The present article comprises an integrative overview of the above issues as a platform for this Special Issue of European Neuropsychopharmacology in which five clinical and five preclinical articles treat individual themes in greater detail. This Volume provides, then, a framework for progress in the understanding – and ultimately control – of the debilitating NS of schizophrenia.
Major depression is a heterogeneous disorder, both in terms of symptoms, ranging from anhedonia to cognitive impairment, and in terms of pathogenesis, with many interacting genetic, epigenetic, ...developmental and environmental causes. Accordingly, it seems unlikely that depressive states could be fully controlled by a drug possessing one discrete mechanism of action and, in the wake of disappointing results with several classes of highly selective agent, multi-modal treatment concepts are attracting attention. As concerns pharmacotherapy, there are essentially two core strategies. First, multi-target antidepressants that act via two or more complementary mechanisms and, second, polypharmacy, which refers to co-administration of two distinct drugs, usually in separate pills. Both multi-target agents and polypharmacy ideally couple a therapeutically unexploited action to a clinically established mechanism in order to enhance efficacy, moderate side-effects, accelerate onset of action and treat a broader range of symptoms. The melatonin MT1/MT2 agonist and 5-HT2C antagonist, agomelatine, which is effective in the short- and long-term treatment of depression, exemplifies the former approach, while evidence-based polypharmacy is illustrated by the adjunctive use of second-generation antipsychotics with serotonin reuptake inhibitors for treatment of resistant depression. Histone acetylation and methylation, ghrelin signalling, inflammatory modulators, metabotropic glutamate-7 receptors and trace amine-associated-1 receptors comprise attractive substrates for new multi-target and polypharmaceutical strategies. The present article outlines the rationale underpinning multi-modal approaches for treating depression, and critically compares and contrasts the pros and cons of established and potentially novel multi-target vs. polypharmaceutical treatments. On balance, the former appear the most promising for the elaboration, development and clinical implementation of innovative concepts for the more effective management of depression.
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