« Neuronal Plasticity Synaptic plasticity is a property of adult as well as developing or young cortex, and reflects how synaptic strength changes with experience ...» Document abstract
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psychology
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13/11/2007
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SummarySynaptic plasticity is a property of adult as well as developing or young cortex, and reflects how synaptic strength changes with experience. Its relevance to psychiatry is seen in the course of the illnesses psychiatrists treat. Clinical research supports the notion that psychiatric illnesses progress and become more refractory to treatment over time. This has been demonstrated most clearly in bipolar disorders and schizophrenia. The expression or severity of an illness changing over time implies an underlying change in the neurobiology of the illness. Neuroscience studies of learning and memory have helped to illuminate the plasticity of adult cortex, which can be used as a blueprint for brain changes associated with psychiatric illnesses. What evidence is there for structural brain changes with learning?
Table of Contents
- Cortical Remodeling Human functional neuroimaging studies demonstrate changes in neural activity patterns as a behavior or a response is learned.
- Neurotransmitters modulate the changes associated with learning and synaptic strengthening.
- Following activation of protein kinases, LTP depends on RNA transcription and protein synthesis and cAMP plays a central role in this process.
- GAP-43 is another molecule important in adult cortical plasticity.
- Progression of Illness In schizophrenia, the longer a person goes without seeking treatment, the more refractory the illness becomes, requiring more time on and higher doses of medication before symptoms remit.
- Not surprisingly, antipsychotic medications induce the expression of c-fos and c-jun.
- These recent observations on the intracellular effects of psychiatric medications have potentially far-reaching implications for the understanding of mental illness and approaches to their treatments.
« messenger pathways is of central importance in considering how neuronal responses are borne out in another well-known model of synaptic plasticity, long-term ...» Document abstract
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biology
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SummaryIn its simplest form, the postsynaptic response to neurotransmitter release can be mediated by a single protein complex. For example, nicotinic acetylcholine receptors are self-contained stimulus-response modules that both detect a stimulus, acetylcholine, and generate a response, passage of ion currents. In a similar vein, other members of this superfamily of ionotropic receptors, including g-aminobutyric acid (GABA) and glutamate receptors, have the ability to function in a manner that is independent of the intracellular signaling pathways discussed. Thus, in contrast to growth factor or G-protein–coupled receptors, which often recruit elaborate cascades to elicit a response, the simplicity of self-sufficient ionotropic receptor complexes represents an optimal design for achieving reliability, precision, and speed. However, this view of ionotropic receptors as insulated from their social environment has had to be abandoned in the face of overwhelming evidence that this class of receptors is dynamically regulated by intraneuronal signaling pathways. Although these receptors do not rely on intraneuronal signaling pathways to operate ion channels, because these channels are an intrinsic feature of the receptor complex the linkage between ligand binding and ion channel gating is nevertheless subject to regulation by the network of intraneuronal signaling pathways just described. For example, phosphorylation of the GABA or glutamate receptors modulates their response to ligand exposure.
Table of Contents
- Long-Term Depression The principle that ion channels are regulated by second messenger pathways is of central importance in considering how neuronal responses are altered by experience.
- Long-Term Potentiation The notion that coactivation of multiple second messenger pathways can have a qualitatively different impact than any one individually is also borne out in another well-known model of synaptic plasticity, long-term potentiation.
- This unusual property of NMDA receptors provides a molecular mechanism for conferring associative properties on long-term potentiation.
- Role of Phosphorylation The associative property of this model of synaptic plasticity has focused attention on deciphering the intraneuronal signaling pathways that mediate the long-term change in synaptic transmission triggered by NMDA receptor stimulation.
- Actions of Psychotropic Drugs In addition to providing insight into the molecular mechanism underlying synaptic plasticity, studies of intraneuronal signaling pathways are also directly relevant to deciphering the mode of action of psychotropic drugs.
- Evidence supporting this theory has been provided by recent studies demonstrating that opiate withdrawal is attenuated in transgenic animals that are deficient in CREB.
« Suggested Readings Benowitz LI, Routtenberg A: GAP-43: An intrinsic determinant of neuronal development and plasticity. Trends Neurosci 20:84, 1997. ...» Document abstract
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psychology
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SummaryThe early postnatal years are marked by a rapid maturation of cognitive, social, and behavioral abilities as infants progress from helplessness to autonomy, and children and adolescents develop more sophisticated ways of thinking. The information and abilities acquired by infants, children, and adolescents are staggering. The impact that these early years have on personality development and behavior is profound, longlasting, and at times, refractory to treatment interventions. The consequences of physical or emotional childhood trauma are seen in every psychiatric practice. For such dramatic cognitive, behavioral, and emotional changes, there must be an underlying neurobiological substrate. Neuroscience is exploring the structural and functional foundations of normal postnatal maturation and how it is impacted by the environment.
Table of Contents
- Postnatal Cortical Maturation The number of cortical synapses changes dramatically in early postnatal life.
- Many neuronal types alter their shape postnatally, corresponding to altered synaptic connections.
- Environmental Effects on Cortical Connections During early life the cortex is fine-tuning its connections dependent on patterns of neural activity caused by environmental input.
- If kittens are deprived of visual input altogether, compensatory changes are seen in the visual areas
- Early environmental manipulations may also impact higher cognitive functioning.
- Critical Periods for Cognition and Emotion The importance of critical periods does not apply solely to visual and language cortices.
- Behavioral studies in monkeys have shown that early childhood experience can have a profound impact on adult adaptation, especially in the context of social stress.
- In humans, there is evidence that early environmental stimulation, even before preschool, improves learning with an effect that lasts for years.
« Suggested Readings Benowitz LI, Routtenberg A: GAP-43: An intrinsic determinant of neuronal development and plasticity. Trends Neurosci 20:84, 1997. ...» Document abstract
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psychology
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SummaryThe wonder of development is that a structure as complex as the human brain originates from a flat sheet of embryologic ectoderm. The final, formed brain shows remarkable order in its predictable cortical layering, its diversity of cortical areas, and the numerous networks linking specific cortical areas and subcortical structures. To have cells choosing to become a certain neuronal type, attaining the correct laminar position, finding the correct target, and expressing the correct neurotransmitters at first seems overwhelmingly difficult. However, the final, breathtakingly complex set of connections in the human brain depends on a series of much simpler decisions as neurons become progressively more restricted in the choices they make. These decisions require the subtle interplay of genetic and environmental factors; much has been learned at a molecular level about these processes. At first glance this information seems most relevant to mental retardation or autistic disorder, in which abnormal brain development results in lifelong disability. However, even schizophrenia is believed to originate in subtle aberrant brain development, and understanding it requires an understanding of its etiology.
Table of Contents
- Neurogenesis and Neural Identity The cerebral cortex possesses an orderly six-layered array of neuronal and glial cell types; layer I is the most superficial layer closest to the meninges, layer VI lies deeper, closest to white matter.
- The first postmitotic neurons leave the neuroepithelium and accumulate beneath the pial surface to form the preplate.
- The microenvironment may also provide other information about a neuron's fate, such as what kind of cortex to become.
- Neuronal Migration Once neurons are born in the ventricular zone, they migrate past earlier born neurons to assume their final laminar position.
- The leading edge of the axon, the growth cone, has an array of molecules on its surface.
- Cell Death Once cortical neurons are created and assume their connections, there is a period of naturally occurring cell death (apoptosis) in widespread areas.
- Implications for Psychiatry What happens when the developmental plan goes awry?
- Such subtle developmental anomalies are being discovered in many animal species.
- One dysfunctional neural network in schizophrenia links the association cortices of the frontal, parietal, and temporal lobes and the limbic cortex and subcortical structures.
- Postmortem morphometric studies of brains from patients with schizophrenia are consistent with in vivo imaging studies.
- A neuron-specific stain for nicotinamide-adenine dinucleotide phosphate-diaphorase (NADPH-d) has been used to study brains from patients with schizophrenia.
- Molecules crucial to normal brain development and postnatal plasticity are being investigated in schizophrenia.
- If abnormal brain development causes schizophrenia, why does onset of symptoms occur in late adolescence or early adulthood?
« LVA channels also appear to be present in neuronal dendrites and may contribute to synaptic integration and synaptic plasticity. ...» Document abstract
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biology
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26/11/2007
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SummaryStructure and Function of Voltage-Gated Ion Channels Voltage-gated ion channels allow the flow of ions in response to changes in membrane voltage and are key elements in neuronal excitation and inhibition. Although ion channels can usually pass more than a single type of ion, voltage-gated channels are named according to the predominant ion that flows when the channel is open. Ion channels that are selective for Na+, K+, Ca2+, or Cl– have been described in neuronal membranes. Certain ion channels that are gated directly by chemical neurotransmitters such as glutamate and acetylcholine are selective for Na+, K+, and Ca2+ but exclude Cl– and are called nonselective cationic channels.
Table of Contents
- Sodium (Na+) Channels Na+ channels are primarily responsible for the fast upstroke of action potentials, although in some neurons Na+ channels also contribute to lower-level depolarizations and pacemaker firing.
- Relations between primary protein structure and ion channel function in Na+ channels have been examined using mutations of specific amino acid residues.
- The net effect is similar to the scorpion toxins. Finally, certain local anesthetic drugs, including lidocaine and procaine, block Na+ channels by binding reversibly to sites within the hydrophobic regions of the ion channel.
- Delayed-rectifier channels open slowly and show little inactivation during prolonged depolarizations.
- M channels represent a class of K+ channels that are activated in a time- and voltage-dependent fashion but are blocked by the neurotransmitter, acetylcholine, acting at muscarinic receptors.
- KATP channels exist in the CNS and appear to be involved in regulating the release of certain neurotransmitters and perhaps in determining the response of some neurons to changes in intracellular energy levels.
- Calcium (Ca2+) Channels Because Ca2+ is involved in numerous cellular events including enzyme activation, gene expression, and neurotransmitter release, the regulation of intracellular Ca2+ levels is of major importance to neurons.
- Most structural information about Ca2+ channels comes from skeletal muscle HVA Ca2+ channels.
« the NMDA receptor serves a critical role in synapse development and plasticity, including the a cascade of cellular events that culminate in neuronal cell death ...» Document abstract
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psychology
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SummaryGlutamate Receptors Glutamate receptors are found throughout the brain and are expressed on both neurons and glia, although not all glutamate receptor subtypes are found on both cell types. Glutamate receptors, sometimes referred to as excitatory amino acid receptors, were initially classified into N-methyl-D-aspartate (NMDA), quisqualate, and kainate receptors on the basis of their preferential activation by these exogenous agonists. More recently, five categories of glutamate receptors (NMDA, kainate, a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid [AMPA], L-2-amino-4-phosphonobutyrate (L-AP4), and trans-1-aminocyclopentane-1,3-dicarboxylic acid [ACPD] receptors) have been established on the basis of pharmacological, electrophysiological, and molecular biological criteria. The L-AP4 receptor type is defined by its agonist and acts as an inhibitory autoreceptor, while the quisqualate receptors of the previous classification have been subdivided by means of more-specific agonists into AMPA and ACPD receptors. AMPA and Kainate receptors are sometimes collectively referred to as non-NMDA receptors. NMDA, kainate and AMPA receptors are ionotropic glutamate receptors; the L-AP4 and ACPD receptors are grouped as metabotropic receptors. Ionotropic receptors are ligand-gated cation-specific channels that are activated rapidly (milliseconds), whereas metabotropic receptors coupled to G proteins and second-messenger systems function more slowly on a scale of several hundred milliseconds to seconds.
Table of Contents
- AMPA Receptors Recent cloning efforts have clearly demonstrated that AMPA and kainate receptors are distinct receptor complexes, although they can be activated by the same agonists.
- Kainate Receptors Although kainate is an effective agonist of AMPA receptors, it also activates its own distinct class of ionotropic receptors, the kainate-preferring receptors.
- NMDA receptors have a number of distinct recognition sites for endogenous and exogenous ligands, each with discrete binding domains. At present there are at least seven pharmacologically distinct sites through which compounds can alter the activity of this receptor.
- Metabotropic Receptors Not as much is known about the last group of glutamate receptors, the metabotropic receptors.
« Overall, the mechanisms underlying the many forms of plasticity of which the family are generally induced from low basal levels upon neuronal stimulation, and ...» Document abstract
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6 word format
Language : english
medical studies
research papers
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26/11/2007
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SummaryAs a first approximation, genes can be defined as stretches of DNA that encode a single protein or a single functional RNA, such as an rRNA or tRNA. There are exceptions to this rule because there are mechanisms, such as alternative splicing of the primary RNA transcript into different mRNAs, that may intervene between a given gene and a finished protein. As a result, in some cases a single gene may actually encode multiple proteins.
Table of Contents
- The chromosomes of eukaryotic cells are so long that they would not fit in the nucleus in their extended form.
- Proteins are not synthesized directly from the DNA that encodes them, but in two sequential processes
- Many genes contain multiple introns and exons that may not be spliced identically in every cell type or in a given cell type at every stage of development.
- Regulatory sequences within DNA control the expression of genes by virtue of their ability to bind specific regulatory proteins.
- Those cis-regulatory elements that specify the site within a gene at which transcription starts, and upon which the complex of proteins that forms the basal transcription apparatus is assembled, are called the basal or core promoter.
- Transcription factors that are tethered to DNA by binding cis-elements often have a modular structure comprised of physically separate domains
- Environmental stimuli are transduced by neurons into neurotransmitter signals.
- CRE binding protein (CREB) is the major protein that binds cAMP response element in most cell types that have been investigated.
- The convergence of multiple signaling pathways (the cAMP and Ca2+ pathways) on a single transcription factor has important implications.
- CREB has also shown to be phosphorylated in the striatum, including the nucleus accumbens, in response to the administration of cocaine and amphetamine, and to be activated in the locus nucleus coeruleus during opiate withdrawal.
- The AP-1 proteins generally bind DNA as heterodimers comprised of one member each of two different families of related proteins, the Fos family and the Jun family.
- IEG mapping is now one of the fundamental tools of functional neuroanatomy.
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