Changes In Neuronal Plasticity Research Articles

Alcohol Induces Parallel Changes in Hippocampal Histone H3 Phosphorylation and c-Fos Protein Expression in Male Rats.

Changes in gene expression associated with alcohol-induced neuroadaptations are controlled in part by post translational histone modifications. Serine 10 phosphorylation of histone H3 (H3S10ph) has been implicated in drug-induced changes in gene expression; however, ethanol (EtOH)'s effects on H3S10ph have yet to be examined in brain. Therefore, hippocampal H3S10ph was examined after acute EtOH exposure and EtOH dependence. Adult male Sprague Dawley rats received an acute exposure of EtOH (0 to 5g/kg) via gavage. Or, rats were made EtOH dependent by administering 25% w/v EtOH every 8hours for 4days following a modified Majchrowicz protocol. In both cases, rats were perfused transcardially and paraformaldehyde-fixed brains were collected and processed for immunohistochemistry to detect H3S10ph or c-fos. Acute EtOH exposure dose dependently altered the number of H3S10ph-positive (+) cells in the hippocampus. Specifically, 1g/kg EtOH increased the number of H3S10ph+ cells in all neuronal layers, while 2.5 and 5g/kg EtOH reduced the number of H3S10ph+ cells, an effect that was confined to the granule cell layer. In EtOH-dependent rats, the number of H3S10ph+ cells in the granule cell layer was reduced by 66% during intoxication; however, H3S10ph+ cells were increased in all neuronal layers during peak withdrawal. Subsequent examination of c-fos, a gene known to be regulated by H3S10ph, revealed that EtOH and withdrawal-associated changes in c-fos closely paralleled changes in H3S10ph. These results suggest that H3S10ph regulates EtOH-mediated changes in c-fos expression, effects that likely have important implications for EtOH-induced changes in hippocampal neuronal plasticity.

Chronic sodium salicylate administration enhances population spike long-term potentiation following a combination of theta frequency primed-burst stimulation and the transient application of pentylenetetrazol in rat CA1 hippocampal neurons

The effect of chronic administration of sodium salicylate (NaSal) on the excitability and synaptic plasticity of the rodent hippocampus was investigated. Repeated systemic treatment with NaSal reliably induced tolerance to the anti-nociceptive effect of NaSal (one i.p. injection per day for 6 consecutive days). Following chronic NaSal or vehicle treatment, a series of electrophysiological experiments on acute hippocampal slices (focusing on the CA1 circuitry) were tested whether tolerance to NaSal would augment pentylenetetrazol (PTZ)-induced long-term potentiation (LTP) and /or epileptic activity, and whether the augmentation was the same after priming activity with a natural stimulus pattern prior to PTZ. We noted an altered synaptic input-to-spike transformation, such that neuronal firing increased after a given synaptic drive. Population spike-LTP (PS-LTP) was increased in the NaSal-tolerant animals, but only when it was induced via a combination of electrical stimulation (theta pattern primed-burst stimulation) and the transient application of PTZ. Identifying and understanding these changes in neuronal excitability and synaptic plasticity following chronic salicylate treatment could prove useful in the clinical diagnosis or treatment of chronic aspirin-induced, or even idiopathic, seizure activity.

Altered NMDA receptor function in primary cultures of hippocampal neurons from mice lacking the Homer2 gene.

N-Methyl-D-Aspartate (NMDA) receptors are inhibited during acute exposure to ethanol and are involved in changes in neuronal plasticity following repeated ethanol exposure. The postsynaptic scaffolding protein Homer2 can regulate the cell surface expression of NMDA receptors in vivo, and mice with a null mutation of the Homer2 gene exhibit an alcohol-avoiding and -intolerant phenotype that is accompanied by a lack of ethanol-induced glutamate sensitization. Thus, Homer2 deletion may perturb the function or acute ethanol sensitivity of the NMDA receptor. In this study, the function and ethanol sensitivity of glutamate receptors in cultured hippocampal neurons from wild-type (WT) and Homer2 knock-out (KO) mice were examined at 7 and 14 days in vitro (DIV) using standard whole-cell voltage-clamp electrophysiology. As compared with wild-type controls, NMDA receptor current density was reduced in cultured hippocampal neurons from Homer2 KO mice at 14 DIV, but not at 7 DIV. There were no genotype-dependent changes in whole-cell capacitance or in currents evoked by kainic acid. The GluN2B-selective antagonist ifenprodil inhibited NMDA-evoked currents to a similar extent in both wild-type and Homer2 KO neurons and inhibition was greater at 7 versus 14 DIV. NMDA receptor currents from both WT and KO mice were inhibited by ethanol (10-100 mM) and the degree of inhibition did not differ as a function of genotype. In conclusion, NMDA receptor function, but not ethanol sensitivity, is reduced in hippocampal neurons lacking the Homer2 gene.

Chronic oxycodone induces integrated stress response in rat brain

BackgroundOxycodone is an opioid that is prescribed to treat multiple types of pain, especially when other opioids are ineffective. Unfortunately, similar to other opioids, repetitive oxycodone administration has the potential to lead to development of analgesic tolerance, withdrawal, and addiction. Studies demonstrate that chronic opioid exposure, including oxycodone, alters gene expression profiles and that these changes contribute to opioid-induced analgesic effect, tolerance and dependence. However, very little is known about opioids altering the translational machinery of the central nervous system. Considering that opioids induce clinically significant levels of hypoxia, increase intracellular Ca2+ levels, and induce the production of nitric oxide and extracellular glutamate transmission, we hypothesize that opioids also trigger a defensive mechanism called the integrated stress response (ISR). The key event in the ISR activation, regardless of the trigger, is phosphorylation of translation initiation factor 2 alpha (eIF2α), which modulates expression and translational activation of specific mRNAs important for adaptation to stress. To test this hypothesis, we used an animal model in which female rats were orally gavaged with 15 mg/kg of oxycodone every 24 h for 30 days.ResultsWe demonstrated increased levels of hsp70 and BiP expression as well as phosphorylation of eIF2α in various rat brain areas after oxycodone administration. Polysomal analysis indicated oxycodone-induced translational stimulation of ATF4 and PDGFRα mRNAs, which have previously been shown to depend on the eIF2α kinase activation. Moreover, using breast adenocarcinoma MCF7 cells, which are known to express the μ-opioid receptor, we observed induction of the ISR pathway after one 24-h treatment with oxycodone.ConclusionsThe combined in vivo and in vitro data suggest that prolonged opioid treatment induces the integrated stress response in the central nervous system; it modulates translational machinery in favor of specific mRNA and this may contribute to the drug-induced changes in neuronal plasticity.

Impairment of adenylyl cyclase-mediated glutamatergic synaptic plasticity in the periaqueductal grey in a rat model of neuropathic pain.

Long-lasting neuropathic pain has been attributed to elevated neuronal plasticity changes in spinal, peripheral and cortical levels. Here, we found that reduced neuronal plasticity in the ventrolateral periaqueductal grey (vlPAG), a midbrain region important for initiating descending pain inhibition, may also contribute to neuropathic pain. Forskolin- and isoproterenol (isoprenaline)-elicited EPSC potentiation was impaired in the vlPAG of a rat model of neuropathic pain induced by spinal nerve injury. Down-regulation of adenylyl cyclase-cAMP- PKA signalling, due to impaired adenylyl cyclase, but not phosphodiesterase, in glutamatergic terminals may contribute to the hypofunction of excitatory synaptic plasticity in the vlPAG of neuropathic rats and the subsequent descending pain inhibition, ultimately leading to long-lasting neuropathic pain. Our results suggest that drugs that activate adenylyl cyclase in the vlPAG have the potential for relieving neuropathic pain. Neuropathic pain has been attributed to nerve injury-induced elevation of peripheral neuronal discharges and spinal excitatory synaptic plasticity while little is known about the contribution of neuroplasticity changes in the brainstem. Here, we examined synaptic plasticity changes in the ventrolateral (vl) periaqueductal grey (PAG), a crucial midbrain region for initiating descending pain inhibition, in spinal nerve ligation (SNL)-induced neuropathic rats. In vlPAG slices of sham-operated rats, forskolin, an adenylyl cyclase (AC) activator, produced long-lasting enhancement of EPSCs. This is a presynaptic effect since forskolin decreased the paired-pulse ratio and failure rate of EPSCs, and increased the frequency, but not the amplitude, of miniature EPSCs. Forskolin-induced EPSC potentiation was mimicked by a β-adrenergic agonist (isoproterenol (isoprenaline)), and prevented by an AC inhibitor (SQ22536) and a cAMP-dependent protein kinase (PKA) inhibitor (H89), but not by a phosphodiesterase (PDE) inhibitor (Ro 20-1724) or an A1 -adenosine antagonist (DPCPX). Both forskolin- and isoproterenol-induced EPSC potentiation was impaired in PAG slices of SNL rats. The SNL group had lower AC, but not PDE, activity in PAG synaptosomes than the sham group. Conversely, IPSCs in vlPAG slices were not different between SNL and sham groups. Intra-vlPAG microinjection of forskolin alleviated SNL-induced mechanical allodynia in rats. These results suggest that SNL leads to inadequate descending pain inhibition resulting from impaired glutamatergic synaptic plasticity mediated by the AC-cAMP-PKA signalling cascade, possibly due to AC down-regulation in the PAG, leading to long-term neuropathic pain.

Restraint stress increases hemichannel activity in hippocampal glial cells and neurons.

Stress affects brain areas involved in learning and emotional responses, which may contribute in the development of cognitive deficits associated with major depression. These effects have been linked to glial cell activation, glutamate release and changes in neuronal plasticity and survival including atrophy of hippocampal apical dendrites, loss of synapses and neuronal death. Under neuro-inflammatory conditions, we recently unveiled a sequential activation of glial cells that release ATP and glutamate via hemichannels inducing neuronal death due to activation of neuronal NMDA/P2X7 receptors and pannexin1 hemichannels. In the present work, we studied if stress-induced glia activation is associated to changes in hemichannel activity. To this end, we compared hemichannel activity of brain cells after acute or chronic restraint stress in mice. Dye uptake experiments in hippocampal slices revealed that acute stress induces opening of both Cx43 and Panx1 hemichannels in astrocytes, which were further increased by chronic stress; whereas enhanced Panx1 hemichannel activity was detected in microglia and neurons after acute/chronic and chronic stress, respectively. Moreover, inhibition of NMDA/P2X7 receptors reduced the chronic stress-induced hemichannel opening, whereas blockade of Cx43 and Panx1 hemichannels fully reduced ATP and glutamate release in hippocampal slices from stressed mice. Thus, we propose that gliotransmitter release through hemichannels may participate in the pathogenesis of stress-associated psychiatric disorders and possibly depression.

Varying time-course of effects of high frequency stimulation of sub-regions of the globus pallidus in patients with parkinson's disease.

Deep brain stimulation of the globus pallidus can be a highly effective treatment for patients with Parkinson's disease (PD), experiencing Levodopa-induced-dyskinesia (LID). Stimulation programming can focus simply on eliminating dyskinesia, or can also attempt to relieve the rigidity, tremor or akinesia of PD itself. In this study, we explored whether additional benefit on the "off" symptoms and signs of PD, could be achieved in post-operative PD patients with good LID control, by making further adjustment to existing stimulation parameters directed towards the more superior electrode contacts, located in the Globus Pallidus pars externa (GPe). Acutely, GPe-DBS led to clear improvement in the akinesia, rigidity and tremor of PD in the off-medication state compared with Globus Pallidus pars interna (GPi) DBS (p=0.003), however this was accompanied by the development of off-medication dyskinesia. Combined GPi-GPe DBS allowed maintained improvement but without dyskinesia. Follow up of patients over the subsequent 6-12 weeks showed gradual loss of this initial improvement. Switching back to GPi-DBS alone provided greater improvement in off medication symptoms than had been observed using the same GPi-DBS setting, 6-12 weeks previously. Benefits on the off-medication symptoms of PD obtained acutely with GPe-DBS are in general not sustained. Similarly, the effects of GPi-DBS on the off medication symptoms of PD, can evolve over short periods of time presumably as a result of changes in network-wide neuronal plasticity. These clinical observations provide further insight into DBS mechanism of action, and can also help inform optimal methods of GPi-DBS programming.

Toxoplasma gondii-induced neuronal alterations.

The zoonotic pathogen Toxoplasma gondii infects over 30% of the human population. The intracellular parasite can persist lifelong in the CNS within neurons modifying their function and structure, thus leading to specific behavioural changes of the host. In recent years, several in vitro studies and murine models have focused on the elucidation of these modifications. Furthermore, investigations of the human population have correlated Toxoplasma seropositivity with changes in neurological functions; however, the complex underlying mechanisms of the subtle behavioural alteration are still not fully understood. The parasites are able to induce direct modifications in the infected cells, for example by altering dopamine metabolism, by functionally silencing neurons as well as by hindering apoptosis. Moreover, indirect effects of the peripheral immune system and alterations of the immune status of the CNS, observed during chronic infection, might also contribute to changes in neuronal connectivity and synaptic plasticity. In this review, we will provide an overview and highlight recent advances, which describe changes in the neuronal function and morphology upon T. gondii infection.

Nanotherapeutic approach for opiate addiction using DARPP-32 gene silencing in an animal model of opiate addiction.

Opiates act on the dopaminergic system of the brain and perturb 32 kDa dopamine and adenosine 3', 5'-monophosphate-regulated phosphoprotein (DARPP-32) function. The DARPP-32 mediated inhibition of protein phosphatase-1 (PP-1) and modulation of transcriptional factor CREB is critical to the changes in neuronal plasticity that result in behavioral responses during drug abuse. To investigate the role of DARPP-32 mediated signaling on withdrawal behavior in a rat model of opiate addiction, we used intracerebral administration of gold nanorods (GNR) complexed to DARPP-32 siRNA to silence DARPP-32 gene expression and measure its effects on the opiate withdrawal syndrome. We hypothesized that DARPP-32 siRNA will suppress the neurochemical changes underlying the withdrawal syndrome and therefore prevent conditioned place aversion by suppressing or removing the constellation of negative effects associated with withdrawal, during the conditioning procedure. Our results showed that opiate addicted animals treated with GNR-DARPP-32 siRNA nanoplex showed lack of condition place aversive behavior consequent to the downregulation of secondary effectors such as PP-1 and CREB which modify transcriptional gene regulation and consequently neuronal plasticity. Thus, nanotechnology based delivery systems could allow sustained knockdown of DARPP-32 gene expression which could be developed into a therapeutic intervention for treating drug addiction by altering reward and motivational systems and interfere with conditioned responses.

Environmental enrichment: Evidence for an unexpected therapeutic influence

Environmental enrichment produces wide-ranging effects in the brain at molecular, cellular, network, and behavioral levels. The changes in neuronal plasticity are driven by changes in neurotransmitters, neurotrophic factors, neuronal morphology, neurogenesis, network properties of the brain, and behavioral correlates of learning and memory. Exposure to an enriched environment has also demonstrated intriguing possibilities for treatment of a variety of neurodegenerative diseases including Huntington's disease, Alzheimer's disease, and Parkinson's disease. The effect of environmental enrichment in epilepsy, a neurodegenerative disorder with pathological neuronal plasticity, is of considerable interest. Recent reports of the effect of environmental enrichment in the Bassoon mutant mouse, a genetic model of early onset epilepsy, provides a significant addition to the literature in this area.

Circadian gating of neuronal functionality: a basis for iterative metaplasticity.

Brain plasticity, the ability of the nervous system to encode experience, is a modulatory process leading to long-lasting structural and functional changes. Salient experiences induce plastic changes in neurons of the hippocampus, the basis of memory formation and recall. In the suprachiasmatic nucleus (SCN), the central circadian (~24-h) clock, experience with light at night induces changes in neuronal state, leading to circadian plasticity. The SCN's endogenous ~24-h time-generator comprises a dynamic series of functional states, which gate plastic responses. This restricts light-induced alteration in SCN state-dynamics and outputs to the nighttime. Endogenously generated circadian oscillators coordinate the cyclic states of excitability and intracellular signaling molecules that prime SCN receptivity to plasticity signals, generating nightly windows of susceptibility. We propose that this constitutes a paradigm of ~24-h iterative metaplasticity, the repeated, patterned occurrence of susceptibility to induction of neuronal plasticity. We detail effectors permissive for the cyclic susceptibility to plasticity. We consider similarities of intracellular and membrane mechanisms underlying plasticity in SCN circadian plasticity and in hippocampal long-term potentiation (LTP). The emerging prominence of the hippocampal circadian clock points to iterative metaplasticity in that tissue as well. Exploring these links holds great promise for understanding circadian shaping of synaptic plasticity, learning, and memory.

Aging somatosensory cortex displays increased density of WFA-binding perineuronal nets associated with GAD-negative neurons

The mechanisms of aging in the brain and the subsequent decrease in cognitive abilities remain elusive. While most studies refer to research conducted in old and senile animals, little is known about the early symptoms of normal, healthy aging. In this study, we examined whether perineuronal nets (PNNs), a special form of extracellular matrix (ECM) tightly associated with neurons that is thought to be involved in limiting neuronal plasticity, undergo changes in density during early aging. Using histochemistry and immunohistochemistry, we found that in middle-aged mice (1-year-old), the density of WFA-binding PNNs in the somatosensory cortex as well as in the visual cortex was increased in comparison to that in young adults (3-month-old). Moreover, in the somatosensory cortex, this increase was not associated with any of the GABAergic neuron types that were examined. We propose that early age-related changes in neuronal plasticity may be associated with this increase and can be conceptualized as the spreading of structural brakes for synaptic rearrangements.

The neuronal activity-driven transcriptome.

Activity-driven transcription is a key event associated with long-lasting forms of neuronal plasticity. Despite the efforts to investigate the regulatory mechanisms that control this complex process and the important advances in the knowledge of the function of many activity-induced genes in neurons, as well as the specific contribution of activity-regulated transcription factors, our understanding of how activity-driven transcription operates at the systems biology level is still very limited. This review focuses on the research of neuronal activity-driven transcription from an "omics" perspective. We will discuss the different high-throughput approaches undertaken to characterize the gene programs downstream of specific activity-regulated transcription factors, including CREB, SRF, MeCP2, Fos, Npas4, and others, and the interplay between epigenetic and transcriptional mechanisms underlying neuronal plasticity changes. Although basic questions remain unanswered and important challenges still lie ahead, the refinement of genome-wide techniques for investigating the neuronal transcriptome and epigenome promises great advances.

Plasticity and Response to Action Observation

Background. Action observation has been suggested as a possible gateway to retraining arm motor function post stroke. However, it is unclear if the neuronal response to action observation is affected by stroke and if it changes during the course of recovery. Objective. To examine longitudinal changes in neuronal activity in a group of patients with subacute stroke when observing and executing a bimanual movement task. Methods. Eighteen patients were examined twice using 3-T functional magnetic resonance imaging; 1 to 2 weeks and 3 months post stroke symptom onset. Eighteen control participants were examined once. Image time series were analyzed (SPM8) and correlated with clinical motor function scores. Results. During action observation and execution, an overlap of neuronal activation was observed in the superior and inferior parietal lobe, precentral gyrus, insula, and inferior temporal gyrus in both control participants and patients (P < .05; false discovery rate corrected). The neuronal response in the observation task increased from 1 to 2 weeks to 3 months after stroke. Most activated clusters were observed in the inferior temporal gyrus, the thalamus and movement-related areas, such as the premotor, supplementary and motor cortex (BA4, BA6). Increased activation of cerebellum and premotor area correlated with improved arm motor function. Most patients had regained full movement ability. Conclusions. Plastic changes in neurons responding to action observation and action execution occurred in accordance with clinical recovery. The involvement of motor areas when observing actions early and later after stroke may constitute a possible access to the motor system.

Deep Brain Stimulation: Are Astrocytes a Key Driver Behind the Scene?

Despite its widespread use, the underlying mechanism of deep brain stimulation (DBS) remains unknown. Once thought to impart a "functional inactivation", there is now increasing evidence showing that DBS actually can both inhibit neurons and activate axons, generating a wide range of effects. This implies that the mechanisms that underlie DBS work not only locally but also at the network level. Therefore, not only may DBS induce membrane or synaptic plastic changes in neurons over a wide network, but it may also trigger cellular and molecular changes in other cells, especially astrocytes, where, together, the glial-neuronal interactions may explain effects that are not clearly rationalized by simple activation/inhibition theories alone. Recent studies suggest that (1) high-frequency stimulation (HFS) activates astrocytes and leads to the release of gliotransmitters that can regulate surrounding neurons at the synapse; (2) activated astrocytes modulate synaptic activity and increase axonal activation; (3) activated astrocytes can signal further astrocytes across large networks, contributing to observed network effects induced by DBS; (4) activated astrocytes can help explain the disparate effects of activation and inhibition induced by HFS at different sites; (5) astrocytes contribute to synaptic plasticity through long-term potentiation (LTP) and depression (LTD), possibly helping to mediate the long-term effects of DBS; and (6) DBS may increase delta-opioid receptor activity in astrcoytes to confer neuroprotection. Together, the plastic changes in these glial-neuronal interactions network-wide likely underlie the range of effects seen, from the variable temporal latencies to observed effect to global activation patterns. This article reviews recent research progress in the literature on how astrocytes play a key role in DBS efficacy.

The Brain Ages Optimally to Model Its Environment: Evidence from Sensory Learning over the Adult Lifespan

The aging brain shows a progressive loss of neuropil, which is accompanied by subtle changes in neuronal plasticity, sensory learning and memory. Neurophysiologically, aging attenuates evoked responses—including the mismatch negativity (MMN). This is accompanied by a shift in cortical responsivity from sensory (posterior) regions to executive (anterior) regions, which has been interpreted as a compensatory response for cognitive decline. Theoretical neurobiology offers a simpler explanation for all of these effects—from a Bayesian perspective, as the brain is progressively optimized to model its world, its complexity will decrease. A corollary of this complexity reduction is an attenuation of Bayesian updating or sensory learning. Here we confirmed this hypothesis using magnetoencephalographic recordings of the mismatch negativity elicited in a large cohort of human subjects, in their third to ninth decade. Employing dynamic causal modeling to assay the synaptic mechanisms underlying these non-invasive recordings, we found a selective age-related attenuation of synaptic connectivity changes that underpin rapid sensory learning. In contrast, baseline synaptic connectivity strengths were consistently strong over the decades. Our findings suggest that the lifetime accrual of sensory experience optimizes functional brain architectures to enable efficient and generalizable predictions of the world.

Persistent changes in neuronal structure and synaptic plasticity caused by proton irradiation

Cranial radiotherapy is used routinely to control the growth of primary and secondary brain tumors, but often results in serious and debilitating cognitive dysfunction. In part due to the beneficial dose depth distributions that may spare normal tissue damage, the use of protons to treat CNS and other tumor types is rapidly gaining popularity. Astronauts exposed to lower doses of protons in the space radiation environment are also at risk for developing adverse CNS complications. To explore the consequences of whole body proton irradiation, mice were subjected to 0.1 and 1Gy and analyzed for morphometric changes in hippocampal neurons 10 and 30days following exposure. Significant dose-dependent reductions (~33%) in dendritic complexity were found, when dendritic length, branching and area were analyzed 30days after exposure. At equivalent doses and times, significant reductions in the number (~30%) and density (50-75%) of dendritic spines along hippocampal neurons of the dentate gyrus were also observed. Immature spines (filopodia, long) exhibited the greatest sensitivity (1.5- to 3-fold) to irradiation, while more mature spines (mushroom) were more resistant to changes over a 1-month post-irradiation timeframe. Irradiated granule cell neurons spanning the subfields of the dentate gyrus showed significant and dose-responsive reductions in synaptophysin expression, while the expression of postsynaptic density protein (PSD-95) was increased significantly. These findings corroborate our past work using photon irradiation, and demonstrate for the first time, dose-responsive changes in dendritic complexity, spine density and morphology and synaptic protein levels following exposure to low-dose whole body proton irradiation.

Prediction of Depression in Schizophrenia: Can serum Levels of BDNF or EGF Help us?

Today, it is known that the levels of neurotrophic factors alter in neuropsychiatric disorders such as major depressive disorder (MDD), schizophrenia, Alzheimer’s disease or Parkinson’s disease. In recent years, some studies demonstrated that MDD may occur as a result of the changes in neuronal plasticity at structural and molecular levels.

The transition from acute to chronic pain: understanding how different biological systems interact

Although pain is an adaptive sensory experience necessary to prevent further bodily harm, the transition from acute to chronic pain is not adaptive and results in the development of a chronic clinical condition. How this transition occurs has been the focus of intense study for some time. The focus of the current review is on changes in neuronal plasticity as well as the role of immune cells and glia in the development of chronic pain from acute tissue injury and pain. Our understanding of the complex pathways that mediate the transition from acute to chronic pain continues to increase. Work in this area has already revealed the complex interactions between the nervous and immune system that result in both peripheral and central sensitization, essential components to the development of chronic pain. Taken together, a thorough characterization of the cellular mechanisms that generate chronic pain states is essential for the development of new therapies and treatments. Basic research leading to the development of new therapeutic targets is promising with the development of chloride extrusion enhancers. It is hoped that one day they will provide relief to patients with chronic pain. A better understanding of how chronic pain develops at a mechanistic level can aid clinicians in treating their patients by showing how the underlying biology of chronic pain contributes to the clinical manifestations of pain. A thorough understanding of how chronic pain develops may also help identify new targets for future analgesic drugs.

Neurobiology of ADHD From Childhood to Adulthood

Objective: To review the pattern of morphological and functional brain changes in both children and adults with ADHD that emerges from the recent literature. In addition, the task of the present review is to explore how to understand the nature of the brain changes. Methods: Literature review. Results: Neuroimaging studies provide a multitude of information that currently allows us to expand the notions of ADHD neurobiology beyond its traditional understanding as a manifestation of frontostriatal dysfunction. They point to disorders of several other areas of the brain, particularly the anterior cingulum, the dorsolateral as well as ventrolateral prefrontal cortex, the orbitofrontal cortex, the superior parietal regions, the caudate nucleus, the thalamus, the amygdala and the cerebellum. Imaging studies point to the persistence of changes in both brain structure and function into adulthood, although there might be a tendency for improvement of caudate nucleus pathology. Changes in neuronal (dendritic) plasticity, which are under the modulatory influence of the dopaminergic system, may be in the background of disorders of brain morphology and anatomical connectivity with subsequent brain dysfunction. Growing evidence suggest that methylphenidate treatment can lead to improvement of brain changes seen in neuroimaging by its positive effect on neuroplasticity. Conclusion: Changes in neuronal plasticity may be behind persisting brain changes in ADHD. Current treatment approaches seem to improve these neuroplastic processes, and, therefore, may have a positive effect on the neuropathology of ADHD.