Glucocorticoids exert a wide range of physiological effects, including the induction of apoptosis in lymphocytes. The progression of glucocorticoid-induced apoptosis is a multi-component process requiring contributions from both genomic and cytoplasmic signaling events. There is significant evidence indicating that the transactivation activity of the glucocorticoid receptor is required for the initiation of glucocorticoid-induced apoptosis. However, the rapid cytoplasmic effects of glucocorticoids may also contribute to the glucocorticoid-induced apoptosis-signaling pathway. Endogenous glucocorticoids shape the T-cell repertoire through both the induction of apoptosis by neglect during thymocyte maturation and the antagonism of T-cell receptor (TCR)-induced apoptosis during positive selection. Owing to their ability to induce apoptosis in lymphocytes, synthetic glucocorticoids are widely used in the treatment of haematological malignancies. Glucocorticoid chemotherapy is limited, however, by the emergence of glucocorticoid resistance. The development of novel therapies designed to overcome glucocorticoid resistance will dramatically improve the efficacy of glucocorticoid therapy in the treatment of haematological malignancies.
glucocorticoid; apoptosis; lymphocyte; haematological malignancy; glucocorticoid resistance
Pheochromocytoma is a very special kind of tumor full of duplicity. On the one hand it represents its own microworld with unique clinical, biochemical and pathological features, while on the other it constitutes a tremendously significant part of whole body system, playing a vital role for practically every organ system. It has a very special character – sometimes like a child it can be sweet and predictable, while at times it can behave like a deadly wild beast, crashing and tearing everything on its path in a fierce rage. It also consists of the amazingly intelligent neuroendocrine cells that possess a magical ability to make miraculous substances of many kinds. But most of all, it is a system that is able to drive our curiosity and the itch of “Cogito, ergo sum” to limitless depths and year by year it still amazes us with new and unexpected discoveries that move our understanding of multiple pathways and metabolic events closer to the ultimate truth. Recent discoveries of succinate dehydrogenase (SHD) and prolyl hydroxylase (PHD) mutations, for example, propelled our understanding of neuroendocrine tumorigenesis as a whole, as well as physiology of mitochondrial respiratory chain and phenomenon of pseudohypoxia in particular. Good old discoveries make their way from dusty repositories to shine with new meaning, appropriate for the current level of knowledge. This acquired wisdom makes us better physicians – knowing the specific expression makeup of catecholamine transporters, GLUTs and SRIFs allows for better tailored imaging and therapeutic manipulations. There are still long ways to go, keeping in mind that pheochromocytoma is but so very special, and we are optimistic and expect many great things to come.
pheochromocytoma; paraganglioma; catecholamines; metanephrines; positron emission tomography
There are numerous examples of sex differences in brain and behavior and in susceptibility to a broad range of brain diseases. For example, gene expression is sexually dimorphic during brain development, adult life, and aging. These differences are orchestrated by the interplay between genetic, hormonal, and environmental influences. However, the molecular mechanisms that underpin these differences have not been fully elucidated. Because recent studies have highlighted the key roles played by epigenetic processes in regulating gene expression and mediating brain form and function, this chapter reviews emerging evidence that shows how epigenetic mechanisms including DNA methylation, histone modifications, and chromatin remodeling, and non-coding RNAs (ncRNAs) are responsible for promoting sexual dimorphism in the brain. Differential profiles of DNA methylation and histone modifications are found in dimorphic brain regions such as the hypothalamus as a result of sex hormone exposure during developmental critical periods. The elaboration of specific epigenetic marks is also linked with regulating sex hormone signaling pathways later in life. Furthermore, the expression and function of epigenetic factors such as the methyl-CpG-binding protein, MeCP2, and the histone-modifying enzymes, UTX and UTY, are sexually dimorphic in the brain. ncRNAs are also implicated in promoting sex differences. For example, X inactivation-specific transcript (XIST) is a long ncRNA that mediates X chromosome inactivation, a seminal developmental process that is particularly important in brain. These observations imply that understanding epigenetic mechanisms, which regulate dimorphic gene expression and function, is necessary for developing a more comprehensive view of sex differences in brain. These emerging findings also suggest that epigenetic mechanisms are, in part, responsible for the differential susceptibility between males and females that is characteristic of a spectrum of neurological and psychiatric disorders.
DNA methylation; Epigenetics; Histone modifications; MicroRNAs; Non-coding RNAs; Sex differences; X chromosome inactivation
Until recently, genetics was thought to play a minor role in the development of Parkinson’s disease (PD). Over the last decade, a number of genes that definitively cause PD have been identified, which has led to the generation of disease models based on pathogenic gene variants that recapitulate many features of the disease. These genetic studies have provided novel insight into potential mechanisms underlying the etiology of PD. This chapter will provide a profile of the genes conclusively linked to PD and will outline the mechanisms of PD pathogenesis implicated by genetic studies. Mitochondrial dysfunction, oxidative stress and impaired ubiquitin-proteasome system function are disease mechanisms that are particularly well supported by genetic studies and are therefore the focus of this chapter.
Dopamine (DA) is a key regulator of action selection and associative learning. The striatum has long been thought to be a major locus of DA action in this process. Although all striatal cell types express G protein-coupled receptors for DA, the effects of DA on principal medium spiny neurons (MSNs) understandably have received the most attention. In the two principal classes of MSN, DA receptor expression diverges, with striatonigral MSNs robustly expressing D1 receptors and striatopallidal MSNs expressing D2 receptors. In the last couple of years, our understanding of how these receptors and the intracellular signalling cascades that they couple to modulate dendritic physiology and synaptic plasticity has rapidly expanded, fuelled in large measure by the development of new optical and genetic tools. These tools also have enabled a rapid expansion of our understanding of the striatal adaptations in models of Parkinson's disease. This chapter highlights some of the major advances in these areas.
Striatum; Dopamine; Synaptic plasticity; Dendritic excitability; Dendritic spines; Parkinson's Disease
Mechanism is at the heart of understanding, and this chapter addresses underlying brain mechanisms and pathways of cognition and the impact of sleep on these processes, especially those serving learning and memory. This chapter reviews the current understanding of the relationship between sleep/waking states and cognition from the perspective afforded by basic neurophysiological investigations. The extensive overlap between sleep mechanisms and the neurophysiology of learning and memory processes provide a foundation for theories of a functional link between the sleep and learning systems. Each of the sleep states, with its attendant alterations in neurophysiology, is associated with facilitation of important functional learning and memory processes. For rapid eye movement (REM) sleep, salient features such as PGO waves, theta synchrony, increased acetylcholine, reduced levels of monoamines and, within the neuron, increased transcription of plasticity-related genes, cumulatively allow for freely occurring bidirectional plasticity (long-term potentiation (LTP) and its reversal, depotentiation). Thus, REM sleep provides a novel neural environment in which the synaptic remodeling essential to learning and cognition can occur, at least within the hippocampal complex. During nonREM sleep Stage 2 spindles, the cessation and subsequent strong bursting of noradrenergic cells and coincident reactivation of hippocampal and cortical targets would also increase synaptic plasticity, allowing targeted bidirectional plasticity in the neocortex as well. In delta nonREM sleep, orderly neuronal reactivation events in phase with slow wave delta activity, together with high protein synthesis levels, would facilitate the events that convert early LTP to long lasting LTP. Conversely, delta sleep does not activate immediate early genes associated with de novo LTP. This nonREM sleep-unique genetic environment combined with low acetylcholine levels may serve to reduce the strength of cortical circuits that activate in the ~50% of delta-coincident reactivation events that do not appear in their waking firing sequence. The chapter reviews the results of manipulation studies, typically total sleep or REM sleep deprivation, that serve to underscore the functional significance of the phenomenological associations. Finally, the implications of sleep neurophysiology for learning and memory will be considered from a larger perspective in which the association of specific sleep states with both potentiation or depotentiation is integrated into mechanistic models of cognition.
Bidirectional plasticity; Long Term Potentiation (LTP); depotentiation; Spindles; Theta; Slow Waves; Acetylcholine (ACh); Norepinephrine (NE); Serotonin (5HT); Memory Consolidation
Breathing, chewing and walking are critical life-sustaining behaviors in mammals that consist essentially of simple rhythmic movements. Breathing movements in particular involve the diaphragm, thorax, and airways but emanate from a network in the lower brain stem. This network can be studied in reduced preparations in vitro and using simplified mathematical models that make testable predictions. An iterative approach that employs both in vitro and in silico models has ruled out canonical mechanisms for respiratory rhythm that involve reciprocal inhibition and pacemaker properties. We present an alternative model in which emergent network properties play the key rhythmogenic role. Specifically, we show evidence that synaptically activated burst-generating conductances – which are only available in the context of network activity – engender robust periodic bursts in respiratory neurons. Because the cellular burst-generating mechanism is linked to network synaptic drive we dub this type of system a group pacemaker.
preBötzinger Complex; pre-Bötzinger Complex; central pattern generator (CPG); metabotropic glutamate receptors; calcium-activated nonspecific cation current; mathematical models; emergent network properties; breathing
Neuromuscular compartments are subvolumes of muscle that have unique biomechanical actions and can be activated singly or in groups to perform the necessary task. Beside unique biomechanical actions, other evidence that supports the neuromuscular compartmentalization of muscles includes segmental reflexes that preferentially excite motoneurons from the same compartment, proportions of motor unit types that differ among compartments and a central partitioning of motoneurons that innervate each compartment. The current knowledge regarding neuromuscular compartments in representative muscles involved in locomotion, respiration and mastication is presented to compare and contrast these different motor systems. Developmental features of neuromuscular compartment formation in these three motor systems are reviewed to identify when these compartments are formed, their innervation patterns and the process of refinement to achieve the adult phenotype. Finally, the role of androgen modulation of neuromuscular compartment maturation in representative muscles of these motor systems is reviewed and the impact of testosterone on specific myosin heavy chain fiber types is discussed based on recent data. In summary, neuromuscular compartments are pre-patterned output elements in muscle that undergo refinement of compartment boundaries and muscle fiber phenotype during maturation. Further studies are needed to understand how these output elements are selectively controlled during locomotion, respiration and mastication.
As the nexus between the nervous system and the skeletomuscular system, motoneurons effect all behaviour. As such, motoneuron activity must be well-regulated so as to generate appropriately timed and graded muscular contractions. Accordingly, motoneurons receive a large number of both excitatory and inhibitory synaptic inputs from various peripheral and central sources. Many of these synaptic contacts arise from spinal interneurons, some of which belong to spinal networks responsible for the generation of locomotor activity. Although the complete definition of these networks remains elusive, it is known that the neural machinery necessary to generate the basic rhythm and pattern of locomotion is contained within the spinal cord. One approach to gaining insights into spinal locomotor networks is to describe those spinal interneurons that directly control the activity of motoneurons, so called “last-order” interneurons. In this review, we briefly survey the different populations of last-order interneurons that have been identified using anatomical, physiological, and genetic methodologies. We discuss the possible roles of these identified last-order interneurons in generating locomotor activity, and in the process, identify particular criteria that may be useful in identifying putative last-order interneurons belonging to spinal locomotor networks.
PMID: 21111202 CAMSID: cams1859
This chapter provides an overview of neurosteroids, especially their impact on the brain, sex differences and therapeutic potentials. Neurosteroids are synthesized within the brain and rapidly modulate neuronal excitability. They are classified as pregnane neurosteroids such as allopregnanolone and allotetrahydrodeoxycorticosterone, and androstane neurosteroids, such as androstanediol and etiocholanone. Neurosteroids such as allopregnanolone are positive allosteric modulators of GABA-A receptors with powerful antiseizure activity in diverse animal models. Neurosteroids increases both synaptic and tonic inhibition. They are endogenous regulators of seizure susceptibility, anxiety and stress. Sulfated neurosteroids such as pregnenolone sulfate, which are negative GABA-Areceptor modulators, are memory-enhancing agents. Sex differences in susceptibility to brain disorders could be due to neurosteroids and sexual dimorphism in specific structures of the human brain. Synthetic neurosteroids that exhibit better bioavailability and efficacy and drugs that enhance neurosteroid synthesis have therapeutic potential in anxiety, epilepsy and other brain disorders. Clinical trials with the synthetic neurosteroid analog ganaxolone in the treatment of epilepsy have been encouraging. Neurosteroidogenic agents that lack benzodiazepine-like side effects show promise in the treatment of anxiety and depression.
Allopregnanolone; androstanediol; deoxycorticosterone; epilepsy; ganaxolone; GABA-A receptor; sex differences; neurosteroid; progesterone; seizure susceptibility; testosterone
The motor symptoms of Parkinson's disease (PD) are due primarily to the degeneration of the dopaminergic neurons in the nigrostriatal pathway. However, several other brain areas and neurotransmitters other than dopamine such as noradrenaline, 5-hydroxytryptamine and acetylcholine are affected in the disease. Moreover, adenosine because of the extensive interaction of its receptors with the dopaminergic system has been implicated in the in the pathophysiology of the disease. Based on the involvement of these nondopaminergic neurotransmitters in PD and the sometimes severe adverse effects that limit the mainstay use of dopamine-based antiparkinsonian treatments, recent assessments have called for a broadening of therapeutic options beyond the traditional dopaminergic drug arsenal.
In this review we describe the interactions between dopamine and adenosine receptors that underpin the preclinical and clinical rationale for pursuing adenosine A2A receptor antagonists as symptomatic and potentially neuroprotective treatment of PD. The review will pay particular attention to recent results regarding specific A2A receptor-receptor interactions and recent findings identifying urate, the end product of purine metabolism, as a novel prognostic biomarker and candidate neuroprotectant in PD.
The pathways of programmed cell death (PCD) are now understood in extraordinary detail at the molecular level. Although much evidence suggests that they are likely to play a role in Parkinson’s disease (PD), the precise nature of that role remains unknown. Two pathways of cell death that are especially well characterized are cyclin-dependent kinase 5-mediated phosphorylation of myocyte enhancer factor 2 and the mitogen-activated protein kinase signalling cascade. Although blockade of these pathways in animals has achieved a truly remarkable degree of neuroprotection of the neuron cell soma, it has not achieved protection of axons. Thus, there is a need to explore beyond the canonical pathways of PCD and investigate mechanisms of axon destruction. We also need to move beyond the narrow classic concept that the mechanisms of PCD are activated exclusively ‘downstream’, following cellular injury. Studies in the genetics of PD suggest that in some forms of the disease, activation may be an early ‘upstream’ event. Additionally, recent observations suggest that cell death in some contexts may not be initiated by injury, but instead by a failure of intrinsic cell survival signalling. These new points of view offer new opportunities for molecular targeting.
Apoptosis; Programmed cell death; LRRK2; DJ-1; Akt; PTEN; GDNF
Simple motor behaviors such as locomotion and respiration involve rhythmic and coordinated muscle movements that are generated by central pattern generator (CPG) networks in the spinal cord and hindbrain. These CPG networks produce measurable behavioral outputs, and thus represent ideal model systems for studying the operational principles that the nervous system uses to produce specific behaviors. Recent advances in our understanding of the transcriptional code that controls neuronal development have provided an entry point into identifying and targeting distinct neuronal populations that make up locomotor CPG networks in the spinal cord. This has spurred the development of new genetic approaches to dissect and manipulate neuronal networks both in the spinal cord and hindbrain. Here we discuss how the advent of molecular genetics together with anatomical and physiological methods has begun to revolutionize studies of the neuronal networks controlling rhythmic motor behaviors in mice.
locomotion; respiration; spinal cord; CPG; interneuron; mouse genetics
Dopamine (DA) replacement therapy with l-DOPA remains the most effective treatment for Parkinson’s disease, but causes dyskinesia (abnormal involuntary movements) in the vast majority of the patients. The basic mechanisms of l-DOPA-induced dyskinesia (LID) have become the object of intense research focusing on neurochemical and molecular adaptations in the striatum. Here we review this vast literature and highlight trends that converge into a unifying pathophysiological interpretation. We propose that the core molecular alteration of striatal neurons in LID consists in an inability to turn down supersensitive signaling responses downstream of DA D1 receptors (where supersensitivity is primarily caused by DA denervation). The sustained activation of intracellular signaling pathways induced by each dose of l-DOPA leads to abnormal cellular plasticity and high bioenergetic expenditure. The over-exploitation of signaling pathways and energy reserves during treatment impairs the ability of striatal neurons to dynamically gate cortically driven motor commands. LID thus exemplifies a disorder where ‘too much’ molecular plasticity leads to plasticity failure in the striatum.
Striatonigral; Striatopallidal; Medium spiny neuron; ERK; MAPK; Transcription; Complications
Several genes that cause familial forms of Parkinson's disease (PD) or similar disorders have been found in recent years. The aim of this review is to cover two broad aspects of the logic of genetics. The first aspect is the recognition that PD can have a genetic basis, either for Mendelian families where genes can be identified because mutations segregate with disease or in populations where more common variants are associated with disease. There are several causal genes for both dominant and recessive forms of parkinsonism, some of which overlap with sporadic PD and some of which have more complex phenotypes. Several of the dominant loci have also been reliably indentified as risk factors for sporadic PD. The second topic is how the study of multiple mutations in any given gene can help understand the role that the protein under investigation plays in PD. Examples will be given of both recessive and dominant genes for parkinsonism, showing how the analysis of multiple gene mutations can be a powerful approach for dissecting out which function(s) are important for the disease process.
The cellular and ionic mechanisms that generate the rhythm in central pattern generator (CPG) networks for simple movements are not well understood. Using vertebrate locomotion, respiration and mastication as exemplars, I describe four main principles of rhythmogenesis: (1) rhythmogenic ionic currents underlie all CPG networks, regardless of whether they are driven by a network pacemaker or an endogenous pacemaker neuron kernel; (2) fast synaptic transmission often evokes slow currents that can affect cycle frequency; (3) there are likely to be multiple and redundant mechanisms for rhythmogenesis in any essential CPG network; and (4) glial cells may participate in CPG network function.
The neural basis for rhythmogenesis in simple behaviors has been studied for almost 100 years, yet we cannot identify with certainty the detailed mechanisms by which rhythmic behaviors are generated in any vertebrate system. Early studies focused on whether locomotor rhythms were generated by a chain of coupled reflexes that require sensory feedback, or by a central neural network. By now there is general agreement that for the major rhythmic behaviors (including locomotion, respiration, and mastication, the subjects of this book), there exist CPG networks within the central nervous system that are able to drive the basic rhythmic behavior in the complete absence of sensory feedback. This of course does not eliminate an important role for sensory feedback, which certainly affects cycle frequency and for some behaviors determines the timing of one phase of the behavior. Given the existence of CPGs, the question of rhythmogenesis can be rephrased to ask how these networks determine the timing of the rhythmic behavior. In this chapter, I focus on cellular and molecular mechanisms that could underlie rhythmogenesis in CPG networks, especially those that drive locomotion, respiration, and mastication.
Central Pattern Generator; rhythmogenesis; bursting; modulation; ion channel; receptor; calcium