In female rats, stimulation of the uterine cervix during mating induces two daily surges of prolactin. Inhibition of hypothalamic dopamine release and stimulation of oxytocin neurons in the paraventricular nucleus (PVN) are required for prolactin secretion. We aim to better understand how stimulation of the uterine cervix is translated into two daily prolactin surges. We hypothesize that noradrenergic neurons in the A1, A2, and locus coeruleus (LC) are responsible for conveying the peripheral stimulus to the PVN. In order to determine whether projections from these neurons to the PVN are activated by cervical stimulation (CS), we injected a retrograde tracer, Fluoro-Gold (FG), into the PVN of ovariectomized rats. Fourteen days after injection, animals were submitted to artificial CS or handling and perfused with a fixative solution. Brains were removed and sectioned from the A1, A2, and LC for c-Fos, tyrosine hydroxylase (TH), and FG triple-labeling using immunohistochemistry. CS increased the percentage of TH/FG+ double-labeled neurons expressing c-Fos in the A1 and LC. CS also increased the percentage of TH+ neurons expressing c-Fos within the A1 and A2, independent of their projections to the PVN. Our data reinforce the significant contributions of the A1 and A2 to carry sensory information during mating, and provide evidence of a functional pathway in which CS activates A1 and LC neurons projecting to the PVN, which is potentially involved in the translation of CS into two daily prolactin surges.
mating; prolactin; locus coeruleus; A1; A2
A prior exposure to isoflurane, a common volatile anesthetic, provides neuroprotection (isoflurane preconditioning). To determine the role of microRNAs in this protection, we performed microRNA array assay on cerebral cortex harvested from rats exposed to isoflurane or isoflurane-exposed rat B35 neuron-like cells. We showed that isoflurane significantly increased microRNA-203 expression in B35 neuron-like cells. The microRNA-203 expression in rat cerebral cortex also trended to increase after isoflurane exposure. Over-expression of microRNA-203 increased the tolerance of B35 cells to oxygen-glucose deprivation and the expression of phospho-Akt, a protein kinase that promotes cell survival. Isoflurane preconditioning also reduced the injury of these cells after oxygen-glucose deprivation. These results suggest that isoflurane preconditioning-induced neuroprotection may involve increased expression of microRNA-203. This finding provides the initial evidence that micoRNA-203 is a target for isoflurane in the brain.
Akt; isoflurane; microRNA; microRNA-203; neuroprotection
Extracellular single unit activity was recorded from medial prefrontal cortex (mPFC) of postpartum dams over the course of 3 days while they engaged in spontaneous pup-directed behaviors and non-specific exploratory behavior. Out of 109 units identified over the course of the experiment, 15 units were observed to be pup-responsive and 15 increased their discharge rates non-specifically while not attending to pups. An association between neuronal activity and typical maternal behaviors (e.g., retrieval, pup-grooming, nursing) was not observed. Instead, brief bouts of snout contact with pups were accompanied by phasic increases and decreases in spike rates. The observed pup contact responsive cells might play a role in processing of sensory feedback from pups or the transmission of modulatory output to other subcortical maternal brain areas.
prelimbic area; medial prefrontal cortex; neuronal firing rate; neuronal activity; maternal behavior; rat; motivation; goal-directed behavior; pups; open field behavior; excitatory neurons; glutamatergic neurons; principal cells; retrieval; rearing
Dopaminergic cell transplantation is an experimental therapy for Parkinson’s disease (PD). It has many potential theoretical advantages over current treatment strategies such as providing continuous local dopaminergic replenishment, eliminating motor fluctuations and medication-induced dyskinesias, slowing down disease progression or even reversing disease pathology in the host. Recent studies also show that dopaminergic cell transplants provide long-term neuromodulation in the basal ganglia that simulates the combined effects of oral dopaminergic therapy and surgical therapies like deep brain stimulation, the contemporary therapeutic approach to advanced PD. However, dopaminergic cell transplantation in PD as not been optimized and current experimental techniques have many drawbacks. In published experiments to date of attempted dopaminergic grafting in PD, the major challenges are unacceptable graft-induced dyskinesias or failure of such grafts to exceed the benefits afforded by sham surgery. A deleterious host immune response to the transplant has been implicated as a major putative cause for these adverse outcomes. This article focuses on recent advances in understanding the immunology of the transplantation in PD and possible methods to overcome adverse events such that we could translate cell replacement strategies into viable clinical treatments in the future.
dopamine; nigrostriatal degeneration; central nervous system; immunosuppression; stem cells; retinal pigment epithelial cells
The endocannabinoid system is emerging as a potential alternative to the dopaminergic system for the treatment of Parkinson’s disease. Like all emerging targets, validation of this system’s potential for treating human Parkinsonism necessitates testing in animal models of the condition. However, if components of the endocannabinoid system are altered by the induction of a Parkinsonian state in animal models, this could have an impact on the interpretation of such preclinical experiments. This study sought to determine if expression of the CB1 subtype of cannabinoid receptor is altered in the two most commonly used rat models of Parkinson’s disease. Parkinsonian lesions were induced by stereotaxic injection of 6-hydroxydopamine into the axons (medial forebrain bundle) or terminals (striatum) of the nigrostriatal pathway. On days 1, 3, 7, 14 and 28 post-lesion, rats were sacrificed and brains were processed for tyrosine hydroxylase and CB1 receptor immunohistochemistry. The CB1 receptor was expressed strongly in the substantia nigra pars reticulata, minimally overlapping with tyrosine hydroxylase immunoreactivity in the pars compacta. Interestingly, while there was little change in CB1 receptor expression following axonal lesion, expression of the receptor was significantly reduced following terminal lesion. Loss of CB1 receptor expression in the pars reticulata correlated significantly with the loss of striatal and nigral volume after terminal lesion indicating this may have been due to 6-hydroxydopamine-induced non-specific damage of striatonigral neurons which are known to express CB1 receptors. Thus, this result has implications for the choice of model and interpretation of studies used to investigate potential cannabinoid-based therapies for Parkinson’s disease as well as striatonigral diseases such as Huntington’s disease and Multiple Systems Atrophy.
Parkinson’s disease; Endocannabinoid system; CB1 receptor; 6-Hydroxydopamine; Substantia nigra
The effects of the administration of the serotonin (5-HT)2A antagonist, M100907, on 5-HT synthesis rates, were evaluated using the α-[14C]methyl-L-tryptophan (α-MTrp) autoradiographic method. In the treatment study, M100907 (10 mg/kg) was injected intraperitoneally 30 min before the α-MTrp injection (30 μCi over 2 min). A single dose of M100907 caused a significant decrease in the synthesis in the anterior olfactory nucleus, accumbens nucleus, frontal cortex, sensory-motor cortex, cingulate cortex, medial caudate-putamen, dorsal thalamus, substantia nigra, inferior collicus, raphe magnus nucleus, superior olive, and raphe pallidus nucleus.
These data suggest that the terminal 5-HT2A receptors are involved in the regulation of 5-HT synthesis in the entire brain. Further, 5-HT synthesis is likely regulated by the 5-HT2A antagonistic property of M100907 in the cortices, anterior olfactory nucleus, caudate putamen, and nucleus accumbens.
PMID: 22056993 CAMSID: cams2891
α-[14C]methyl-L-tryptophan; Serotonin synthesis rate; 5-HT2A receptor antagonist; M100907; Autoradiography
Flinders Sensitive Line (FSL) rat is as an animal model of depression with altered parameters of the serotonergic (5-HT) system function (5-HT synthesis rates, tissue concentrations, release, receptor density and affinity), as well as an altered sensitivity of these parameters to different 5-HT based antidepressants. The effects of acute and chronic treatments with the 5-HT1B agonist, CP-94253 on 5-HT synthesis, in the FSL rats and the Flinders Resistant Line (FRL) controls were measured using α-[14C]methyl-L-tryptophan (α-MTrp) autoradiography. CP-94253 (5 mg/kg), or an adequate volume of saline, was injected i.p. as a single dose in the acute experiment or delivered via the subcutaneously implanted osmotic minipump (5 mg/kg/day for 14 days) in the chronic experiment. The acute treatment with CP-94253 significantly decreased the 5-HT synthesis in both the FRL and FSL rats, with a more widespread effect in the FRL rats. Chronic treatment with CP-94253 significantly decreased 5-HT synthesis in the FRL rats, while 5-HT synthesis in the FSL rats was significantly increased throughout the brain. In both the acute and chronic experiment, the FRL rats had higher brain 5-HT synthesis rates, relative to the FSL rats.
The shift in the direction of the treatment effect from acute to chronic, using the 5-HT1B agonist, CP-94253, on 5-HT synthesis in the FSL model of depression, with an opposite effect on the control FRL rats, suggests the differential adaptation of the 5-HT system in the FSL and FRL rats to chronic stimulation of 5-HT1B receptors.
PMID: 22542420 CAMSID: cams2894
Flinders Sensitive Line; Flinders Resistant Line; Depression; 5-HT1B receptor; α-MTrp; Autoradiography; Serotonin synthesis rate
The spinocerebellar ataxias (SCA) are dominantly inherited disorders that primarily affect coordination of motor function but also frequently involve other brain functions. The models described in this review address mechanisms of trinucleotide-repeat expansions, particularly those relating to polyglutamine expression in the mutant proteins. Modeling chronic late-onset human ataxias in mice is difficult because of their short life-span. While this potential hindrance has been partially overcome by using over-expression of the mutant gene, and/or worsening of the mutation by increasing the length of the trinucleotide repeat expansion, interpretation of results from such models and extrapolation to the human condition should be cautious. Nevertheless, genetically engineered murine models of these diseases have enhanced our understanding of the pathogenesis of many of these conditions. A common theme in many of the polyglutamine-repeat diseases is nuclear localization of mutant protein, with resultant effects on gene regulation. Conditional mutant models and transgenic knock-down therapy have demonstrated the potential for reversibility of disease when production of mutant protein is halted. Several other genetically engineered murine models of SCA also have begun to show utility in the identification and assessment of more classical drug-based therapeutic modalities.
spinocerebellar ataxia; Purkinje cell; transgenic mice; trinucleotide repeat disease
Parkinson’s disease (PD) is the most common neurodegenerative movement disorder, affecting more than 1% of the population over age 60. The most common feature of PD is a resting tremor, though there are many systemic neurological effects, such as incontinence and sleep disorders. PD is histopathologically identified by the presence of Lewy bodies (LB), proteinaceous inclusions constituted primarily by α-synuclein. To date, there is no effective treatment to slow or stop disease progression. To help understand disease pathogenesis and identify potential therapeutic targets, many genetic mouse models have been developed. By far the most common of these models are the wildtype and mutant α-synuclein transgenic mice, because α-synuclein was the first protein shown to have a direct effect on PD pathogenesis and progression. There are many other gene-disrupted or -mutated models currently available, which are based on genetic anomalies identified in the human disease. In addition, there are also models which examine genes that may contribute to disease onset or progression but currently have no identified causative PD mutations. These genes are part of signaling pathways important for maintaining neuronal function in the nigrostriatal pathway. This review will summarize the most commonly used of the genetic mouse models currently available for PD research. We will examine how these models have expanded our understanding of PD pathogenesis and progression, as well as aided in identification of potential therapeutic targets in this disorder.
Neurofibromatosis type 1 (NF1), the most common genetic disorder affecting the human nervous system, is characterized by the development of multiple benign Schwann cell tumors in skin and large peripheral nerves. These neoplasms, which are termed dermal and plexiform neurofibromas respectively, have distinct clinical courses; of particular note, plexiform, but not dermal, neurofibromas often undergo malignant progression to form malignant peripheral nerve sheath tumors (MPNSTs), the most common malignancy occurring in NF1 patients. In recent years, a number of genetically engineered mouse models have been created to investigate the molecular mechanisms driving the pathogenesis of these tumors. These models have been designed to address key questions including: 1) whether NF1 loss in the Schwann cell lineage is essential for tumorigenesis; 2) what cell type(s) in the Schwann cell lineage gives rise to dermal neurofibromas, plexiform neurofibromas and MPNSTs; 3) how the tumor microenvironment contributes to neoplasia; 4) what additional mutations contribute to neurofibroma-MPNST progression; 5) what role different neurofibromin-regulated Ras proteins play in this process and 6) how dysregulated growth factor signaling facilitates PNS tumorigenesis. In this review, we summarize the major findings from each of these models and their limitations as well as how discrepancies between these models may be reconciled. We also discuss how information gleaned from these models can be synthesized to into a comprehensive model of tumor formation in peripheral nervous system and consider several of the major questions that remain unanswered about this process.
Neurofibromatosis; Schwann cell; tumor suppressor gene; tumor microenvironment; aberrant growth factor signaling
Alzheimer’s disease (AD) is the most common cause of dementia, affecting 35 million people today. The search for new treatments is made ever more urgent by prospects for increasing prevalence due to population aging. Mouse models are one of the most important research tools for finding new treatments for AD. Here, we review those models. We begin by briefly reviewing the AD genetics on which mouse models are based and then consider the most common mouse models of AD, including mice transgenic for human amyloid precursor protein (hAPP) and beta-amyloid (Aβ), mice expressing mutant presenilin genes, mice modeling tau’s role in AD, and apolipoprotein E models. The discussion highlights key features and important differences between these mouse models. We conclude with a discussion about the role of AD mouse models in the translational pipeline.
Alzheimer’s disease; Amyloid-beta; Presenilin; Tau; Apolipoprotein E (ApoE); Behavior; Transgenic
Neovascular ocular diseases as exemplified by proliferative diabetic retinopathy(PDR), exudative age-related macular degeneration (AMD), and retinopathy of prematurity (ROP) are severe diseases affecting all age groups in the US. We asked whether a small molecule, carboxyamidotriazole (CAI) known for its anti-angiogenic and anti-tumor effects and its ability to be administered orally in humans, could have anti-angiogenic effects in ocular in vitro and in vivo angiogenesis models. The anti-proliferative effects of CAI were examined by BrdU incorporation using human retinal and dermal endothelial cells and human pigment epithelial cells. The effect of CAI was determined using the Matrigel tube formation assay. The mouse model of choroidal neovascularization (CNV) initiated by laser rupture of Bruch’s membrane was used to quantify in vivo effects of aqueous beta-hydroxypropyl cyclodextrin (bHPCD) formulations of CAI on neovascularization. The pharmacokinetics (PK) of CAI after intravitreal administration bHPCD-CAI were studied undertaken in rabbit. The intravitreal toxicology of bHPCD-CAI was also examined in rat ocular tissue. We observed that CAI treatment of human endothelial cells decreased cell proliferation in a dose dependent manner. In the in vivo tests bHPCD-CAI treatment reduced choroidal neovascular lesion volume, also in a dose-dependent manner. The intravitreal PK of bHPCD-CAI demonstrated that highly efficacious concentrations of CAI are reached in the vitreous compartment. No ocular toxicology was observed with intravitreous injection of CAI. These studies support the potential of developing intravitreal CAI in an bHPCD ocular formulation for treatment of proliferative retinopathies in humans.
angiogenesis; therapy; choroidal neovascularization; endothelial cell; animal model; carboxyamidotriazole
Huntington’s disease (HD) is a progressive neurodegenerative disease characterized by progressive atrophy of the striatum, cerebral cortex, and white matter tracks. Major pathological hallmarks of HD include neuronal loss, primarily in the striatum, and dendritic anomalies in surviving striatal neurons. Although many mouse models of HD have been generated, their success at reproducing all pathological features of the disease is not fully known. Previously, we demonstrated extensive striatal neuronal loss and striatal atrophy at 20–26 months of age in a knock-in (KI) mouse model of HD. To further investigate this model, which carries a human exon 1 with ~119 CAG repeats inserted into the mouse gene (initially 140 repeats), we have examined whether these mice exhibit the atrophy and neuronal anomalies characteristic of HD. Stereological analyses revealed no changes in the striatal volume of male and female homozygote mice at 4 months, however striatal atrophy was already present at 12 months in both sexes. Analysis of cortical and corpus callosum volume in male homozygotes revealed a loss in corpus callosum volume by 20–26 months. At this later age, the surviving striatal neurons displayed extensive loss of spines in distal branch orders that affected both immature and mature spines. Mirroring late stage HD striatal neuronal morphology, the striatal neurons at this late age also showed reduced dendritic complexity, as revealed by Sholl analysis. Tyrosine hydroxylase immunoreactivity was also decreased in the striatum of 20–26 month old KI mice, suggesting an alteration in striatal inputs. These data further indicate that CAG140 homozygote KI mice exhibit HD-like pathological features and are a useful model to test the effects of early and/or sustained administration of novel neuroprotective treatments.
Golgi stain; stereology; volume; huntingtin; cortex; corpus callosum
The cytoarchitecture and cortical connections of the anterior cingulate, medial and dorsal premotor, and precentral region are investigated using the Nissl and NeuN staining method and the fluorescent retrodgrade tract tracing technique. There is a gradual stepwise laminar change in the cytoarchitectonic organization from the proisocortical anterior cingulate region, through the lower and upper banks of the cingulate sulcus, to the dorsolateral isocortical premotor and precentral motor regions of the frontal lobe. These changes are characterized by a gradational emphasis on the lower stratum layers (V and VI) in the proisocortical cingulate region to the upper stratum layers (II and III) in the premotor and precentral motor region. This is accompanied by a progressive widening of layers III and VI, a poorly delineated border between layers III and V and a sequential increase in the size of layer V neurons culminating in the presense of giant Betz cells in the precentral motor region. The overall patterns of corticocortical connections paralleled the sequential changes in cytoarchitectonic organization. The proisocortical areas have connections with cingulate motor, supplementary motor, premotor and precentral motor areas on the one hand and have widespread connections with the frontal, parietal, temporal and multimodal association cortex and limbic regions on the other. The dorsal premotor areas have connections with the proisocortical areas including cingulate motor areas and supplementary motor area on the one hand, and premotor and precentral motor cortex on the other. Additionally, this region has significant connections with posterior parietal cortex and limited connections with prefrontal, limbic and multimodal regions. The precentral motor cortex also has connections with the proisocortical areas and premotor areas. Its other connections are limited to the somatosensory regions of the parietal lobe. Since the isocortical motor areas on the dorsal convexity mediate voluntary motor function, their close connectional relationship with the cingulate areas form a pivitol limbic-motor interface that could provide critical sources of cognitive, emotional and motivational influence on complex motor function.
Cerebral Cortex; Frontal Lobe; Limbic System; Motivation; Motor Behavior
Methylphenidate (MPD) is a psychostimulant that enhances dopaminergic neurotransmission in the central nervous system by using mechanisms similar to cocaine and amphetamine. The mode of action of brain circuitry responsible for an animal’s neuronal response to MPD is not fully understood. The nucleus accumbens (NAc) has been implicated in regulating the rewarding effects of psychostimulants. The present study used permanently implanted microelectrodes to investigate the acute and chronic effects of MPD on the firing rates of NAc neuronal units in freely behaving rats. On experimental day 1 (ED1), following a saline injection (control), a 30 minute baseline neuronal recording was obtained immediately followed by a 2.5 mg/kg i.p. MPD injection and subsequent 60 min neuronal recording. Daily 2.5 mg/kg MPD injections were given on ED2 through ED6 followed by 3 washout days (ED7 to 9). On ED10, neuronal recordings were resumed from the same animal after a saline and MPD (rechallenge) injection exactly as obtained on ED1. Sixty-seven NAc neuronal units exhibited similar wave shape, form and amplitude on ED1 and ED10 and their firing rates were used for analysis. MPD administration on ED1 elicited firing rate increases and decreases in 54% of NAc units when compared to their baselines. Six consecutive MPD administrations altered the neuronal baseline firing rates of 85% of NAc units. MPD rechallenge on ED10 elicited significant changes in 63% of NAc units. These alterations in firing rates are hypothesized to be through mechanisms that include D1 and D2-like DA receptor induced cellular adaptation and homeostatic adaptations/deregulation caused by acute and chronic MPD administration.
Methylphenidate; Nucleus accumbens; Electrophysiology; Behavior sensitization/tolerance
The polyunsaturated fatty acids (PUFAs), arachidonic acid (AA, 20:4n-6) and docosahexaenoic acid (DHA, 22:6n-3), important second messengers in brain, are released from membrane phospholipid following receptor-mediated activation of specific phospholipase A2 (PLA2) enzymes. We developed an in vivo method in rodents using quantitative autoradiography to image PUFA incorporation into brain from plasma, and showed that their incorporation rates equal their rates of metabolic consumption by brain. Thus, quantitative imaging of unesterified plasma AA or DHA incorporation into brain can be used as a biomarker of brain PUFA metabolism and neurotransmission. We have employed our method to image and quantify effects of mood stabilizers on brain AA/DHA incorporation during neurotransmission by muscarinic M1,3,5, serotonergic 5-HT2A/2C, dopaminergic D2-like (D2, D3, D4) or glutamatergic N-methyl-D-aspartic acid (NMDA) receptors, and effects of inhibition of acetylcholinesterase, of selective serotonin and dopamine reuptake transporter inhibitors, of neuroinflammation (HIV-1 and lipopolysaccharide) and excitotoxicity, and in genetically modified rodents. The method has been extended for the use with positron emission tomography (PET), and can be employed to determine how human brain AA/DHA signaling and consumption are influenced by diet, aging, disease and genetics.
arachidonic acid; bipolar disorder; brain imaging; docosahexaenoic acid; mood stabilizers; neuroinflammation
Parkinson’s disease (PD) is characterized by loss of nigrostriatal neurons and depletion of dopamine. This pathological feature leads to alterations to basal ganglia circuitry and subsequent motor disability. Pharmacological dopamine replacement therapy with medications such as levodopa ameliorates the symptoms of PD but can lead to motor complications known as drug-induced dyskinesias. We have recently shown that clinically hemiparkinsonian rhesus monkeys do not develop levodopa-induced dyskinesias despite chronic intermittent exposure and significant unilateral loss of nigrostriatal neurons and dopamine. It is currently unclear what mechanisms prevent the onset of dyskinesias in these animals. However, based on our study and results from previous lesioning studies in both the rat and monkey models of PD, we hypothesize that one potential mechanism that may prevent the genesis of dyskinesias in these animals is interhemispheric inhibition. Two potential interhemispheric connections that may modulate dyskinesias are the interhemispheric nigrostriatal and corticostriatal pathways. Few investigators have examined the interhemispheric nigrostriatal and corticostriatal connections and the functional role they may play in drug-induced dyskinesias in PD. Therefore, in the following review, we assess the neuroanatomical, electrophysiological and behavioral properties of these interhemispheric connections. Future studies evaluating these interhemispheric striatal pathways and the pathophysiological changes that occur to these pathways in the dyskinetic state are warranted to further develop treatments that prevent or mitigate drug-induced dyskinesias in PD.
basal ganglia; nigrostriatal degeneration; movement disorders; dopamine replacement therapy
Measures that quantify the relationship between two or more brain signals are drawing attention as neuroscientists explore the mechanisms of large-scale integration that enable coherent behavior and cognition. Traditional Fourier-based measures of coherence have been used to quantify frequency-dependent relationships between two signals. More recently, several off-line studies examined Phase-Locking Value (PLV) as a possible feature for use in brain-computer interface (BCI) systems. However, only a few individuals have been studied and full statistical comparisons among the different classes of features and their combinations have not been conducted. The present study examines the relative BCI performance of spectral power, coherence, and PLV, alone and in combination. The results indicate that spectral power produced classification at least as good as PLV, coherence, or any possible combination of these measures. This may be due to the fact that all three measures reflect mainly the activity of a single signal source (i.e., an area of sensorimotor cortex). This possibility is supported by the finding that EEG signals from different channels generally had near-zero phase differences. Coherence, PLV, and other measures of inter-channel relationships may be more valuable for BCIs that use signals from more than one distinct cortical source.
Brain-Computer Interface; Sensorimotor Rhythms; Coherence; Phase-Locking Value
Although there is increasing clinical acceptance of acupuncture and electroacupuncture (EA) as a treatment of substance abuse-related disorders, our understanding of this treatment remains incomplete. Previous clinical and pre-clinical studies have shown that acupuncture and EA are effective in reducing ethanol consumption. Recent studies have shown that Sprague–Dawley (SD) rats under an intermittent-access two-bottle choice drinking procedure (IE procedure) voluntarily drank high amounts of ethanol. However, an effect of EA on ethanol consumption of the SD rats under this drinking procedure has not been demonstrated.
In the present study, we demonstrated that SD rats escalated their ethanol intake and subsequently developed ethanol dependence under the IE procedure. A single low (2 Hz), but not high frequency (100 Hz) EA treatment applied at the bilateral acupoint Zusanli (ST36), but not at the tail reduced voluntary intake of, and preference for ethanol, but not sucrose. Furthermore, repeated EA treatments decreased the intake of and preference for ethanol, without resulting in a rebound increase in ethanol intake when the EA treatments were terminated. These observations indicate that EA may be a useful treatment for alcohol abuse.
Acupuncture; Addiction; Alcohol dependence; Sprague-Dawley rats; treatment
Epidemiologic studies support a connection between organophosphate pesticide exposures and subsequent risk of Parkinson’s Disease (PD). We used differentiating, neuronotypic PC12 cells to compare organophosphates (chlorpyrifos, diazinon), an organochlorine (dieldrin) and a metal (Ni2+) for their effects on the transcription of PD-related genes. Both of the organophosphates elicited significant changes in gene expression but with differing patterns: chlorpyrifos evoked both up- and downregulation whereas diazinon elicited overall reductions in expression. Dieldrin was without effect but Ni2+ produced a pattern resembling that of diazinon. We then exposed neonatal rats to chlorpyrifos or diazinon for the first four days after birth and examined the expression of PD-related genes in the brainstem and forebrain. Chlorpyrifos had no significant effect whereas diazinon produced significant increases and decreases in expression of the same PD genes that were targeted in vitro. Our results provide some of the first evidence for a mechanistic relationship between developmental organophosphate exposure and the genes known to confer PD risk in humans; but they also point to disparities between different organophosphates that reinforce the concept that their neurotoxic actions do not rest solely on their shared property as cholinesterase inhibitors. The parallel effects of diazinon and Ni2+ also show how otherwise unrelated developmental neurotoxicants can nevertheless produce similar outcomes by converging on common molecular pathways, further suggesting a need to examine metals such as Ni2+ as potential contributors to PD risk.
Chlorpyrifos; Developmental neurotoxicity; Diazinon; Dieldrin; Gene transcription; Microarray; Nickel; Organophosphate insecticides; Organochlorine insecticides; Parkinson’s disease
Smoking during pregnancy increases the risk of preterm delivery, which in turn necessitates the common use of glucocorticoids to prevent respiratory distress syndrome. Accordingly, there is a substantial population exposed conjointly to fetal nicotine and glucocorticoids (typically dexamethasone). We administered nicotine to pregnant rats throughout gestation, using a regimen (3 mg/kg/day by osmotic minipump) that maintains plasma nicotine levels within the range seen in smokers; on gestational days 17, 18 and 19, we gave 0.2 mg/kg of dexamethasone. We assessed norepinephrine levels in three brain regions (frontal/parietal cortex, brainstem, cerebellum) throughout adolescence, young adulthood and later adulthood, and contrasted the persistent effects with comparable measures in peripheral tissues (heart, liver). In adolescence, males showed initial deficits in the frontal/parietal cortex with either dexamethasone alone or the combined treatment, with resolution to normal by young adulthood; the group exposed to both nicotine + dexamethasone showed subsequent elevations that emerged in full adulthood and persisted through five months of age, an effect not seen with either agent separately. In females, the combined exposure produced an initial deficit that resolved by young adulthood, without any late-emerging changes. We did not see comparable effects in the other brain regions or peripheral tissues. This indicates that nicotine exposure sensitizes the developing brain to the adverse effects of dexamethasone treatment, producing sex-selective changes in innervation and/or activity of specific noradrenergic circuits. The fact that the combined treatment produced greater effects points to potentially worsened neurobehavioral outcomes after pharmacotherapy of preterm labor in the offspring of smokers.
Brain development; Dexamethasone; Glucocorticoids; Nicotine; Norepinephrine; Preterm delivery
Proper expression of synaptic NMDA receptors (NMDARs) is necessary to regulate synaptic Ca2+ influx and the induction the long-term potentiation (LTP) in the mammalian hippocampus. Previously we reported that expressing the A-type K+ channel subunit Kv4.2 in CA1 neurons of organotypic slice cultures reduced synaptic NR2B-containing NMDAR expression and completely blocked LTP induced by a pairing protocol. As pretreatment with an NMDAR antagonist (APV) overnight blocked the reduction of NR2B-containing receptors in neurons expressing EGFP-labeled Kv4.2 (Kv4.2g), we hypothesized that LTP would be rescued in Kv4.2g neurons by overnight treatment with APV. We report here that the overnight APV pretreatment in Kv4.2g-expressing neurons only partially restored potentiation. This partial potentiation was completely blocked by inhibition of the CAMKII kinase. These results indicate that A-type K+ channels must regulate synaptic integration and plasticity through another mechanism in addition to their regulation of synaptic NR2 subunit composition. We suggest that dendritic excitability, which is regulated by Kv4.2 expression, also contributes to synaptic plasticity.
Synaptic plasticity; A-type K+ channel; Kv4.2; LTP; NMDA receptor; CaMKII
Exaggerated reactivity to food cues in obese women appears to be mediated in part by a hyperactive reward system that includes the nucleus accumbens, amygdala, and orbitofrontal cortex. The present study used fMRI to investigate whether differences between 12 obese and 12 normal-weight women in reward-related brain activation in response to food images can be explained by changes in the functional interactions between key reward network regions. A two-step path analysis/General Linear Model approach was used to test whether there were group differences in network connections between nucleus accumbens, amygdala, and orbitofrontal cortex in response to high- and low-calorie food images. There was abnormal connectivity in the obese group in response to both high- and low-calorie food cues compared to normal-weight controls. Compared to controls, the obese group had a relative deficiency in the amygdala’s modulation of activation in both orbitofrontal cortex and nucleus accumbens, but excessive influence of orbitofrontal cortex’s modulation of activation in nucleus accumbens. The deficient projections from the amygdala might relate to suboptimal modulation of the affective/emotional aspects of a food’s reward value or an associated cue’s motivational salience, whereas increased orbitofrontal cortex to nucleus accumbens connectivity might contribute to a heightened drive to eat in response to a food cue. Thus, it is possible that not only greater activation of the reward system, but also differences in the interaction of regions in this network may contribute to the relatively increased motivational value of foods in obese individuals.
connectivity; food cues; obesity; reward system
Neuregulin-1 (NRG1) is a trophic and differentiation factor that signals through ErbB receptor tyrosine kinases to regulate nervous system development. Previous studies have demonstrated that NRG1 affects plasticity at glutamatergic synapses in principal glutamatergic neurons of the hippocampus and frontal cortex; however, immunohistochemical and genetic analyses strongly suggest these effects are indirect and mediated via ErbB4 receptors on GABAergic interneurons. Here, we used cultured cerebellar granule cells (CGCs) that express ErbB4 to analyze the cell-autonomous effects of NRG1 stimulation on glutamatergic function. These cultures have the advantage that they are relatively homogenous and consist primarily of granule neurons that express ErbB4. We show that acute NRG1 treatment does not affect whole-cell AMPA or NMDA receptor (NMDAR) mediated currents in CGCs at 10–12 days in vitro. NRG1 also does not affect the frequency or amplitude of spontaneous AMPAR or NMDAR mediated miniature excitatory post-synaptic currents (mEPSCs). To further investigate the effects of NRG1 on activity-dependent plasticity of glutamatergic synapses in CGCs, we characterized the effects of activation of synaptic NMDAR with high-glyine/0 Mg2+ on AMPAR-mEPSC frequency and amplitude. We show that high-glycine induces a form of chemical long-term potentiation (chemLTP) in CGCs characterized by an increase in AMPAR-mEPSC frequency but not amplitude. Moreover, NRG1 induces a decrease in AMPAR-mEPSC frequency following chemLTP, but does not affect AMPAR-mEPSC amplitude. CGCs in our cultures conditions express low levels of GluR1, in contrast to dissociated hippocampal cultures, but do express the long isoform of GluR4. This study provides first evidence that (1) high-glycine can induce plasticity at glutamatergic synapses in CGCs, and (2) that acute NRG1/ErbB-signaling can regulate glutamatergic plasticity in CGCs. Taken together with previous reports, our results suggest that, similar to Schaeffer collateral to CA1 synapses, NRG1 effects are activity dependent and mediated via modulation of synaptic AMPARs.
cerebellar granule neurons; neuregulin-1; ErbB; chemical LTP; synaptic plasticity