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Reduced striatal dopamine underlies the attention system dysfunction in neurofibromatosis-1 mutant mice
Abstract and Figures
Learning and behavioral abnormalities are among the most common clinical problems in children with the neurofibromatosis-1 (NF1) inherited cancer syndrome. Recent studies using Nf1 genetically engineered mice (GEM) have been instructive for partly elucidating the cellular and molecular defects underlying these cognitive deficits; however, no current model has shed light on the more frequently encountered attention system abnormalities seen in children with NF1. Using an Nf1 optic glioma (OPG) GEM model, we report novel defects in non-selective and selective attention without an accompanying hyperactivity phenotype. Specifically, Nf1 OPG mice exhibit reduced rearing in response to novel objects and environmental stimuli. Similar to children with NF1, the attention system dysfunction in these mice is reversed by treatment with methylphenidate (MPH), suggesting a defect in brain catecholamine homeostasis. We further demonstrate that this attention system abnormality is the consequence of reduced dopamine (DA) levels in the striatum, which is normalized following either MPH or l-dopa administration. The reduction in striatal DA levels in Nf1 OPG mice is associated with reduced striatal expression of tyrosine hydroxylase, the rate-limited enzyme in DA synthesis, without any associated dopaminergic cell loss in the substantia nigra. Moreover, we demonstrate a cell-autonomous defect in Nf1+/- dopaminergic neuron growth cone areas and neurite extension in vitro, which results in decreased dopaminergic cell projections to the striatum in Nf1 OPG mice in vivo. Collectively, these data establish abnormal DA homeostasis as the primary biochemical defect underlying the attention system dysfunction in Nf1 GEM relevant to children with NF1.
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... For example, mice with conditional Nf1 knockout in the central nervous system (CNS) (BLBP-Cre; Nf1 flox/flox ) are smaller than controls due to reduced growth hormone secretion secondary to disruption of hypothalamic Ras-independent neurofibromin regulation of cAMP [76] . Importantly, these findings provide insight into the mechanisms underlying the reduced stature present in NF1 individuals (20%-30% of NF1 adults have a height below the 3rd centile) [77,78] . ...
... The other allele produces WT neurofibromin, but this is insufficient to maintain normal cellular function [ Figure 1]. This is termed haploinsufficiency, and evidence supports that this alone (i.e., without a 'second hit') can result in certain NF1 manifestations, such as CD/SD, osteopenia, osteoporosis, short stature, macrocephaly, and vasculopathy [5,10,11,32,78,[120][121][122] . ...
... Decreased bone mineral density, which underlies osteopenia and osteoporosis, is detected in up to 50% of NF1 individuals at an early age [78] . An increased incidence of fractures has also been reported [78] . ...
Neurofibromatosis type 1 (NF1) is a genetic disorder with a wide range of manifestations and severity. Currently, the few available NF1 treatments target specific manifestations, with no available therapies targeted to correct the underlying driver of all NF1 manifestations. Evidence supports that haploinsufficiency in NF1 caused by a decreased amount of wild-type (WT) neurofibromin in all Nf1+/- cells directly causes or facilitates a range of NF1 manifestations. Consequently, NF1 haploinsufficiency correction therapy (NF1-HCT) represents a potentially effective approach to treat some NF1 manifestations. NF1-HCT would normalize the level of WT neurofibromin in all NF1-haploinsufficient cells, including those integral to the NF1 phenotype such as Schwann cells (SCs), melanocytes, neurons, bone cells, and cells of the tumor microenvironment. This would correct altered cellular signaling pathways and, in turn, restore normal function to cells with a retained WT allele. NF1-HCT will not restore WT neurofibromin in NF1-/- cells; however, by restoring function in the surrounding Nf1+/- microenvironment cells, NF1-HCT is predicted to have a beneficial effect on NF1-/- cells. NF1-HCT is expected to have a clinical effect in some NF1 manifestations, as follows: (i) prevention, or delay of onset, of potential manifestations; and (ii) reversal, or halting/slowing progression, of established manifestations. This review describes the rationale for NF1-HCT, including specific NF1 considerations (e.g., NF1 clinical phenotype, neurofibromin function/regulation, NF1 mutational spectrum, genotype-phenotype correlation, and the impact of haploinsufficiency in NF1), HCT in other haploinsufficient diseases, potential NF1-HCT drug treatment strategies, and the potential advantages/challenges of NF1-HCT.
... In general, our findings are in line with some animal studies. In fact, experimental data about abnormalities of the circadian clock control in Drosophila models of NF1 (45) and on the defects in the regulation of RAS activity, cAMP generation, and dopamine homeostasis have been proposed as key mechanisms for sleep disruption in NF1 children (54). In addition, dopamine alterations may result in attentional and learning deficits (54)(55)(56), which could be explained by the reduced functional connectivity between the striatum and the frontoparietal networks and increased striatal functional connectivity with the limbic network in NF1 children (57). ...
... In fact, experimental data about abnormalities of the circadian clock control in Drosophila models of NF1 (45) and on the defects in the regulation of RAS activity, cAMP generation, and dopamine homeostasis have been proposed as key mechanisms for sleep disruption in NF1 children (54). In addition, dopamine alterations may result in attentional and learning deficits (54)(55)(56), which could be explained by the reduced functional connectivity between the striatum and the frontoparietal networks and increased striatal functional connectivity with the limbic network in NF1 children (57). Specifically, the dopaminergic pathway alteration can indeed cause the higher PLMI in NF1 reported in our study considering that periodic limb movement disorder and the restless leg syndrome tend usually to beneficiate from dopaminergic receptor agonists treatment (58,59) or iron supplementation in developmental age (60) due to functional interactions among iron, epicidin, and dopamine production (18). ...
Background
Neurofibromatosis type 1 (NF1) is a genetic disease that alters neurodevelopment. We aimed to analyze the sleep macrostructure of a sample of children affected by NF1 without neurocognitive co-morbidities and MRI reports of unidentified bright objects (UBOs).
Methods
A 100 pre-pubertal children participated in the cross-sectional study: 50 subjects were children diagnosed with NF1 and 50 subjects were typically developing healthy children (TDC). All participants underwent polysomnographic evaluation through which conventional sleep parameters were collected: Total sleep time (TST), Sleep latency (SOL), first REM latency (FRL), number of stage shifts/h (SS/h), number of awakenings/h (AWN/h), wake after sleep onset (WASO%), sleep efficiency percentage (SE%), percentage of sleep time spent in sleep stages 1 (N1%) and 2 (N2%), slow-wave sleep (N3%), and REM sleep (REM%). Additionally, nocturnal respiratory events such as apnea/hypopnea index (AHI), oxygen desaturation index (ODI), and periodic limb movement index (PLMI) were recorded.
Results
Neurofibromatosis type 1 children showed a reduction in sleep duration parameters (TST; p < 0.001), sleep efficiency (SE%; p < 0.001), and stage N2% (p < 0.001). Moreover, the number of awakenings per hour (AWN/h), wake after sleep onset (WASO%), and respiratory events such as AHI, ODI, and PLMI resulted higher in NF1 vs. TDC children.
Conclusion
The data showed that the sleep macrostructure differs between NF1 and TDC children. These findings suggest that the evaluation of sleep may provide useful support in corroborating the diagnosis and offers additional therapeutic management perspectives in NF1 and genetic neurodevelopmental disorders in general.
... With age, deficits in cognitive function remain or decline [11], and new issues arise including an increased risk for depression and dementia [12][13][14][15]. The mechanisms for NF1 neurological manifestations are not clear, but significant insights have been obtained using adult mouse genetic models; spatial learning issues have been attributed to abnormal GABA signaling [16] and attention system dysfunction to striatal dopaminergic neurons [17,18]. However, drugs that improve neurological phenotypes in models have shown inconclusive results in clinical trials [19,20], which precludes final recommendations for NF1 treatment [21][22][23]. ...
Simple Summary
Most neurofibromatosis type 1 (NF1) patients present with neurological issues in parallel with abnormal brain white matter and myelin. Although links for NF1 neuropathophysiology and abnormal myelin were proposed long ago, no current data can openly support or refute this idea. Various studies suggest that Nf1 mutations affect myelin biology and function, but any impact on learning/memory remains unclear. Here, we show that mice with an Nf1 mutation induced in adult myelinating cells present learning, but not memory, issues in a voluntary fine motor skill test, the complex wheel (CW). The specific parameters shaping CW learning curves are differentially impacted in an Nf1 mutation dose- and gender-dependent manner and are responsive to nitric oxide modulation. Fate analyses of Nf1 mutant cells support links between defective myelin and fine motor learning issues. Our results diversify the potential therapeutic targets and windows of time for NF1 treatments that restore or improve myelin function.
Abstract
Neurofibromatosis type 1 (NF1) is caused by mutations in the NF1 gene. The clinical presentation of NF1 includes diverse neurological issues in pediatric and adult patients, ranging from learning disabilities, motor skill issues, and attention deficit disorder, to increased risk of depression and dementia. Preclinical research suggests that abnormal neuronal signaling mediates spatial learning and attention issues in NF1; however, drugs that improve phenotypes in models show inconclusive results in clinical trials, highlighting the need for a better understanding of NF1 pathophysiology and broader therapeutic options. Most NF1 patients show abnormalities in their brain white matter (WM) and myelin, and links with NF1 neuropathophysiology have been suggested; however, no current data can clearly support or refute this idea. We reported that myelin-targeted Nf1 mutation impacts oligodendrocyte signaling, myelin ultrastructure, WM connectivity, and sensory–motor behaviors in mice; however, any impact on learning and memory remains unknown. Here, we adapted a voluntary running test—the complex wheel (CW; a wheel with unevenly spaced rungs)—to delineate fine motor skill learning curves following induction of an Nf1 mutation in pre-existing myelinating cells (pNf1 mice). We found that pNf1 mutant females experience delayed or impaired learning in the CW, while proper learning in pNf1 males is predominantly disrupted; these phenotypes add complexity to the gender-dependent learning differences in the mouse strain used. No broad differences in memory of acquired CW skills were detected in any gender, but gene-dose effects were observed at the studied time points. Finally, nitric oxide signaling regulation differentially impacted learning in wild type (WT)/pNf1, male/female mice. Our results provide evidence for fine motor skill learning issues upon induction of an Nf1 mutation in mature myelinating cells. Together with previous connectivity, cellular, and molecular analyses, these results diversify the potential treatments for neurological issues in NF1.
... Visual acuity and contrast testing was completed using the Virtual Optomotor System (VOS; Cerebral Mechanics Inc.) adapted from previous methods [33,34]. Testing assessed the sharpness of vision and the ability to distinguish between the foreground and background at P47. ...
Mucopolysaccharidosis (MPS) IIIB, also known as Sanfilippo Syndrome B, is a devastating childhood disease. Unfortunately, there are currently no available treatments for MPS IIIB patients. Yet, animal models of lysosomal storage diseases have been valuable tools in identifying promising avenues of treatment. Enzyme replacement therapy, gene therapy, and bone marrow transplant have all shown efficacy in the MPS IIIB model systems. A ubiquitous finding across rodent models of lysosomal storage diseases is that the best treatment outcomes resulted from intervention prior to symptom onset. Therefore, the aim of the current study was to identify early markers of disease progression in the MPS IIIB mouse model as well as examine clinically-relevant behavioral domains not yet explored in this model. We observed reduced maternal isolation-induced ultrasonic vocalizations in MPS IIIB mice relative to controls, as well as disruption in a number of the spectrotemporal features. MPS IIIB also exhibited disrupted thermoregulation during the first two postnatal weeks without any differences in body weight. The developmental trajectories of gait were largely normal. In early adulthood, we observed intact visual acuity and sociability yet a more submissive phenotype and increased aggressive behavior relative to controls. MPS IIIB mice showed greater inhibition of startle in response to a pretone with a decrease in overall startle response and reduced cued fear memory. MPS IIIB also weighed significantly more than controls throughout adulthood and showed larger whole brain volumes and normalized regional volumes with intact tissue integrity as measured with magnetic resonance and diffusion tensor imaging, respectively. Together, these results indicate disease markers are present as early as the first two weeks postnatal in this model. Further, this model recapitulates social, sensory and fear-related clinical features. Our study using a mouse model of MPS IIIB provides essential baseline information that will be useful in future evaluations of potential treatments.
... Children with NF1 and mice with a heterogenous mutation in the Nf1 gene (Nf1 +/− ) demonstrate striatal dysfunction and disrupted corticocortical connectivity in the default network (Shofty et al., 2019). In addition, reduced striatal dopamine is associated with attention system dysfunction in Nf1 mutant mice and is reversed by methylphenidate (Brown et al., 2010), which implicates the striatum in attentional deficits seen in NF1. Thus, disruption resulting from neurofibromin deficiency may result in aberrant connectivity within frontostriatal regions subserving the habituation abnormalities in NF1. ...
Atypical habituation to repetitive information has been commonly reported in Autism Spectrum Disorder (ASD) but it is not yet clear whether similar abnormalities are present in Neurofibromatosis Type 1 (NF1). We employed a cross-syndrome design using a novel eye tracking paradigm to measure habituation in preschoolers with NF1, children with idiopathic ASD and typically developing (TD) children. Eye movements were recorded to examine fixation duration to simultaneously presented repeating and novel stimuli. Children with NF1 showed a bias for longer look durations to repeating stimuli at the expense of novel stimuli, and slower habituation in NF1 was associated with elevated ASD traits. These findings could indicate aberrant modulation of bottom-up attentional networks that interact with the emergence of ASD phenotypes.
Background
Mucopolysaccharidosis (MPS) IIIB, also known as Sanfilippo Syndrome B, is a devastating childhood disease. Unfortunately, there are currently no available treatments for MPS IIIB patients. Yet, animal models of lysosomal storage diseases have been valuable tools in identifying promising avenues of treatment. Enzyme replacement therapy, gene therapy, and bone marrow transplant have all shown efficacy in the MPS IIIB model systems. A ubiquitous finding across rodent models of lysosomal storage diseases is that the best treatment outcomes resulted from intervention prior to symptom onset. Therefore, the aim of the current study was to identify early markers of disease in the MPS IIIB mouse model as well as examine clinically-relevant behavioral domains not yet explored in this model.
Methods
Using the MPS IIIB mouse model, we explored early developmental trajectories of communication and gait, and later social behavior, fear-related startle and conditioning, and visual capabilities. In addition, we examined brain structure and function via magnetic resonance imaging and diffusion tensor imaging.
Results
We observed reduced maternal isolation-induced ultrasonic vocalizations in MPS IIIB mice relative to controls, as well as disruption in a number of the spectrotemporal features. MPS IIIB also exhibited disrupted thermoregulation during the first two postnatal weeks without any differences in body weight. The developmental trajectories of gait were largely normal. In early adulthood, we observed intact visual acuity and sociability yet a more submissive phenotype, increased aggressive behavior, and decreased social sniffing relative to controls. MPS IIIB mice showed greater inhibition of startle in response to a pretone with a decrease in overall startle response and reduced cued fear memory. MPS IIIB also weighed significantly more than controls throughout adulthood and showed larger whole brain volumes and normalized regional volumes with intact tissue integrity as measured with magnetic resonance and diffusion tensor imaging, respectively.
Conclusions
Together, these results indicate disease markers are present as early as the first two weeks postnatal in this model. Further, this model recapitulates social, sensory and fear-related clinical features. Our study using a mouse model of MPS IIIB provides essential baseline information that will be useful in future evaluations of potential treatments.
Background
Neurofibromatosis Type 1 is a genetic condition diagnosed in infancy that substantially increases the likelihood of a child experiencing cognitive and developmental difficulties, including Autism Spectrum Disorder (ASD) and Attention Deficit Hyperactivity Disorder (ADHD). One of the most characteristic cognitive differences observed in children with NF1 is in visuospatial processing, but whether this contributes to broader difficulties with cognitive and learning skills is unclear. To address this question requires longitudinal prospective studies from infancy, where the relation between visuospatial difficulties and cognitive development can be mapped over time.
Methods
We report data from 28 infants with NF1 tested longitudinally at 5, 10 and 14 months compared to cohorts of 29 typical likelihood infants (with no history of NF1 or ASD and/or ADHD), and 123 infants with a family history of ASD and/or ADHD. We used an eyetracking battery to measure visual spatial attention.
Results
Infants with NF1 demonstrated intact social orienting, but slower development of endogenous visual foraging. This slower development presented as prolonged engagement with a salient stimulus in a static display relative to typically developing infants. In terms of exogenous attention shifting, NF1 infants showed faster saccadic reaction times than typical likelihood infants. However, the NF1 group demonstrated a slower developmental improvement from 5 to 14 months of age. Individual differences in foraging and saccade times were concurrently related to visual reception abilities within the full infant cohort (NF1, typical likelihood and those with a family history of ASD/ADHD).
Conclusions
Our results provide preliminary evidence that alterations in saccadic reaction time and visual foraging may contribute to learning difficulties in infants with NF1; social orienting and engagement develop typically in these infants.
Evidence for myelin regulating higher-order brain function and disease is rapidly accumulating; however, defining cellular/molecular mechanisms remains challenging partially due to the dynamic brain physiology involving deep changes during development, aging, and in response to learning and disease. Furthermore, as the etiology of most neurological conditions remains obscure, most research models focus on mimicking symptoms, which limits understanding of their molecular onset and progression. Studying diseases caused by single gene mutations represents an opportunity to understand brain dys/function, including those regulated by myelin. Here, we discuss known and potential repercussions of abnormal central myelin on the neuropathophysiology of Neurofibromatosis Type 1 (NF1). Most patients with this monogenic disease present with neurological symptoms diverse in kind, severity, and onset/decline, including learning disabilities, autism spectrum disorders, attention deficit and hyperactivity disorder, motor coordination issues, and increased risk for depression and dementia. Coincidentally, most NF1 patients show diverse white matter/myelin abnormalities. Although myelin-behavior links were proposed decades ago, no solid data can prove or refute this idea yet. A recent upsurge in myelin biology understanding and research/therapeutic tools provides opportunities to address this debate. As precision medicine moves forward, an integrative understanding of all cell types disrupted in neurological conditions becomes a priority. Hence, this review aims to serve as a bridge between fundamental cellular/molecular myelin biology and clinical research in NF1.
The mesolimbic dopamine system is an evolutionarily conserved set of brain circuits that plays a role in attention, appetitive behavior, and reward processing. In this circuitry, ascending dopaminergic projections from the ventral midbrain innervate targets throughout the limbic forebrain, such as the ventral striatum/nucleus accumbens (NAc). Dopaminergic signaling in the NAc has been widely studied for its role in behavioral reinforcement, reward prediction error encoding, and motivational salience. Less well characterized is the role of dopaminergic neurotransmission in the response to surprising or alerting sensory events. To address this, we used the genetically encoded dopamine sensor dLight1 and fiber photometry to explore the ability of striatal dopamine release in to encode the properties of salient sensory stimuli in mice, such as threatening looming discs. Here, we report that lateral NAc (LNAc) dopamine release encodes the rate and magnitude of environmental luminance changes rather than visual stimulus threat level. This encoding is highly sensitive, as LNAc dopamine could be evoked by light intensities that were imperceptible to human experimenters. We also found that light-evoked dopamine responses are wavelength-dependent at low irradiances, independent of the circadian cycle, robust to previous exposure history, and involve multiple phototransduction pathways. Thus, we have further elaborated the mesolimbic dopamine system's ability to encode visual information in mice, which is likely relevant to a wide body of scientists employing light sources or optical methods in behavioral research involving rodents.
Metabolic syndrome (MetS), characterized by hyperglycemia, obesity, and hyperlipidemia, can increase the risk of developing late-onset dementia. Recent studies in patients and mouse models suggest a putative link between hyperphosphorylated tau, a component of Alzheimer's disease-related dementia (ADRD) pathology, and cerebral glucose hypometabolism. Impaired glucose metabolism reduces glucose flux through the hexosamine metabolic pathway triggering attenuated O-linked N-acetylglucosamine (O-GlcNAc) protein modification. The goal of the current study was to investigate the link between cognitive function, tau pathology, and O-GlcNAc signaling in an aging mouse model of MetS, agouti KKAy+/- . Male and female C57BL/6, non-agouti KKAy-/- , and agouti KKAy+/- mice were aged 12-18 months on standard chow diet. Body weight, blood glucose, total cholesterol, and triglyceride were measured to confirm the MetS phenotype. Cognition, sensorimotor function, and emotional reactivity were assessed for each genotype followed by plasma and brain tissue collection for biochemical and molecular analyses. Body weight, blood glucose, total cholesterol, and triglyceride levels were significantly elevated in agouti KKAy+/- mice versus C57BL/6 controls and non-agouti KKAy-/- . Behaviorally, agouti KKAy+/- revealed impairments in sensorimotor and cognitive function versus age-matched C57BL/6 and non-agouti KKAy-/- mice. Immunoblotting demonstrated increased phosphorylated tau accompanied with reduced O-GlcNAc protein expression in hippocampal-associated dorsal midbrain of female agouti KKAy+/- versus C57BL/6 control mice. Together, these data demonstrate that impaired cognitive function and AD-related pathology are associated with reduced O-GlcNAc signaling in aging MetS KKAy+/- mice. Overall, our study suggests that interaction of tau pathology with O-GlcNAc signaling may contribute to MetS-induced cognitive dysfunction in aging.
The Cre/lox system is widely used in mice to achieve cell-type-specific gene expression. However, a strong and universally responding system to express genes under Cre control is still lacking. We have generated a set of Cre reporter mice with strong, ubiquitous expression of fluorescent proteins of different spectra. The robust native fluorescence of these reporters enables direct visualization of fine dendritic structures and axonal projections of the labeled neurons, which is useful in mapping neuronal circuitry, imaging and tracking specific cell populations in vivo. Using these reporters and a high-throughput in situ hybridization platform, we are systematically profiling Cre-directed gene expression throughout the mouse brain in several Cre-driver lines, including new Cre lines targeting different cell types in the cortex. Our expression data are displayed in a public online database to help researchers assess the utility of various Cre-driver lines for cell-type-specific genetic manipulation.
The symptoms of childhood attention-deficit hyperactivity disorder (ADHD) cover the domains of cognition, impulsivity and motor control, and often embody motivational/emotional features. Prevalence of the combined-type disorder may decrease with age, but the former features predominate increasingly through adolescence to adulthood. The widespread innervation through the CNS by fibers containing serotonin (5-HT) means that, as cause or effect, it is likely that 5-HT is involved where function in these domains is impaired. The relative success of treatment with catecholaminergic agents has overshadowed investigation of the reasons for the partial response of half of these patients. This chapter suggests that anomalous 5-HT function may provide one potential explanation. The best evidence lies with the high heritability of the disorder, where several genes with small effect contribute to the availability of 5-HT and its metabolism. Extra-neuronal availability is under the control of enzymes responsible for 5-HT synthesis, and its removal depends on breakdown or reuptake. Alleles are expressed in cases with ADHD that disturb this availability; they can be over- or under-expressed, depending on phenotype (e.g., impulsivity). The effect of altered levels of 5-HT is mediated by the expression of pre- and postsynaptic receptors of the 5-HT1 and 5-HT2 families. Neuropsychological and neurophysiological studies show that the processes affected range from perception, through attention to motivationally guided learning and mood. While the function of a range of brain regions may be involved, the thalamus and frontal lobes are taken as potentially influential examples. Study in this field is in its infancy, and many putative interactions (e.g., between genes, gene/environment, co-morbid problems, development and motor function) require closer investigation.
Individuals with the neurofibromatosis type 1 (NF1) inherited cancer syndrome exhibit neuronal dysfunction that predominantly affects the CNS. In this report, we demonstrate a unique vulnerability of CNS neurons, but not peripheral nervous system (PNS) neurons, to reduced Nf1 gene expression. Unlike dorsal root ganglion neurons, Nf1 heterozygous (Nf1+/-) hippocampal and retinal ganglion cell (RGC) neurons have decreased growth cone areas and neurite lengths, and increased apoptosis compared to their wild-type counterparts. These abnormal Nf1+/- CNS neuronal phenotypes do not reflect Ras pathway hyperactivation, but rather result from impaired neurofibromin-mediated cAMP generation. In this regard, elevating cAMP levels with forskolin or rolipram treatment, but not MEK (MAP kinase kinase) or PI3-K (phosphatidylinositol 3-kinase) inhibition, reverses these abnormalities to wild-type levels in vitro. In addition, Nf1+/- CNS, but not PNS, neurons exhibit increased apoptosis in response to excitotoxic or oxidative stress in vitro. Since children with NF1-associated optic gliomas often develop visual loss and Nf1 genetically engineered mice with optic glioma exhibit RGC neuronal apoptosis in vivo, we further demonstrate that RGC apoptosis resulting from optic glioma in Nf1 genetically engineered mice is attenuated by rolipram treatment in vivo. Similar to optic glioma-induced RGC apoptosis, the increased RGC neuronal death in Nf1+/- mice after optic nerve crush injury is also attenuated by rolipram treatment in vivo. Together, these findings establish a distinctive role for neurofibromin in CNS neurons with respect to vulnerability to injury, define a CNS-specific neurofibromin intracellular signaling pathway responsible for neuronal survival, and lay the foundation for future neuroprotective glioma treatment approaches.
The long-term response to chronic stress is variable, with some individuals developing maladaptive functioning, although other "resilient" individuals do not. Stress reduces neurogenesis in the dentate gyrus subgranular zone (SGZ), but it is unknown if stress-induced changes in neurogenesis contribute to individual vulnerability. Using a chronic social defeat stress model, we explored whether the susceptibility to stress-induced social avoidance was related to changes in SGZ proliferation and neurogenesis. Immediately after social defeat, stress-exposed mice (irrespective of whether they displayed social avoidance) had fewer proliferating SGZ cells labeled with the S-phase marker BrdU. The decrease was transient, because BrdU cell numbers were normalized 24 h later. The survival of BrdU cells labeled before defeat stress was also not altered. However, 4 weeks later, mice that displayed social avoidance had more surviving dentate gyrus neurons. Thus, dentate gyrus neurogenesis is increased after social defeat stress selectively in mice that display persistent social avoidance. Supporting a functional role for adult-generated dentate gyrus neurons, ablation of neurogenesis via cranial ray irradiation robustly inhibited social avoidance. These data show that the time window after cessation of stress is a critical period for the establishment of persistent cellular and behavioral responses to stress and that a compensatory enhancement in neurogenesis is related to the long-term individual differences in maladaptive responses to stress.
Despite enormous progress in the past few years the specific contribution of newly born granule cells to the function of the adult hippocampus is still not clear. We hypothesized that in order to solve this question particular attention has to be paid to the specific design, the analysis, and the interpretation of the learning test to be used. We thus designed a behavioral experiment along hypotheses derived from a computational model predicting that new neurons might be particularly relevant for learning conditions, in which novel aspects arise in familiar situations, thus putting high demands on the qualitative aspects of (re-)learning.
Poor control of attention-related and motor processes, often associated with behavioural or cognitive impulsivity, are typical features of children and adults with attention-deficit hyperactivity disorder (ADHD). Until recently clinicians have observed little need to improve on or add to the catecholaminergic model for explaining the features of ADHD. Recent genetic and neuroimaging studies however provide evidence for separate contributions of altered dopamine (DA) and serotonin (5-HT) function in this disorder. Genetic studies imply that for both DA and 5-HT systems variants may frequently occur in ADHD for neurotransmitter uptake, synthesis and breakdown functions. The separate distributions in the brain of mesolimbic DA transporter and mesocortical DA D4 binding sites, both strongly implicated in ADHD, draws attention to potentially differential contributions from the 5-HT system. However, the evidence here points less towards an anatomical differentiation, as towards one in terms of inhibitory/facilitatory pre/post-synaptic location of receptors in the 5-HT(1) and 5-HT(2) families. While the monoamine metabolite levels excreted in ADHD are often correlated, this may well flow from a starting point where 5-HT activity is anomalously higher or lower than the generally lower than normal levels for DA. It appears that perhaps both situations may arise reflecting different diagnostic subgroups of ADHD, and where impulsive characteristics of the subjects reflect externalizing behaviour or cognitive impulsivity. For these features there is clear evidence that DA and 5-HT neuronal systems can and do interact anomalously in ADHD at the level of the soma, the terminals and at a distance. Interactions mediated by macroglia are also likely. However, it remains difficult to ascribe specific mechanisms to their effects (in potentially different subgroups of patients) from this relatively new field of study that has as yet produced rather heterogeneous results.
Oxidative injury has been implicated in the etiology of Parkinson's disease (PD). Gypenosides (GPs), the saponins extract derived from the Gynostemma pentaphyllum, has various bioactivities. In this study, GPs was investigated for its neuroprotective effects on the 1-methyl-4-phenylpyridinium ion (MPP+)-induced oxidative injury of dopaminergic neurons in primary nigral culture. It was found that GPs pretreatment, cotreatment or posttreatment significantly and dose-dependently attenuated MPP+-induced oxidative damage, reduction of dopamine uptake, loss of tyrosine hydrolase (TH)-immunopositive neurons and degeneration of TH-immunopositive neurites. However, the preventive effect of GPs was more potential than its therapeutical effect. Most importantly, the neuroprotective effect of GPs may be attributed to GPs-induced strengthened antioxidation as manifested by significantly increased glutathione content and enhanced activity of glutathione peroxidase, catalyze and superoxide dismutase in nigral culture. The neuroprotective effects of GPs are specific for dopaminergic neurons and it may have therapeutic potential in the treatment of PD.
We examined the effects of voluntary (16 weeks of wheel running) and forced (16 weeks of treadmill running) exercise on memory-related behavior, hippocampal volume, thioflavine-stained plaque number, and soluble Abeta levels in brain tissue in the Tg2576 mouse model of Alzheimer's disease (AD). Voluntary running animals spent more time investigating a novel object in a recognition memory paradigm than all other groups. Also, voluntary running animals showed fewer thioflavine S stained plaques than all other groups, whereas forced running animals showed an intermediate number of plaques between voluntary running and sedentary animals. Both voluntary and forced running animals had larger hippocampal volumes than sedentary animals. However, levels of soluble Abeta-40 or Abeta-42 did not significantly differ among groups. The results indicate that voluntary exercise may be superior to forced exercise for reducing certain aspects of AD-like deficits - i.e., plaque deposition and memory impairment, in a mouse model of AD.
• Neurologic and cognitive function in neurofibromatosis type 1 (NF1) were assessed in a controlled pilot study of 13 pairs of siblings aged 6 to 27 years. One subject in each pair was affected with NF1, and the other, the control subject, was unaffected. Subjects with evidence of focal central nervous system disease were excluded. The 13 subjects with NF1 had no excess of mental retardation, attention-deficit disorder, or specific learning disorders (using Wilcoxon's Signed Rank Test and McNemar's Test for Symmetry). These subjects, however, had significantly higher scores for subtle neurologic abnormalities (21 vs 6) and significantly lower full-scale IQ scores (94 vs 105) than their unaffected siblings. The IQ scores of the affected subjects were not clustered at the lower end of the scale but showed a slight downward shift in distribution compared with those of their siblings. In addition, a visual-spatial orientation deficit was present in eight of nine affected subjects so evaluated. The findings suggest that subjects with NF1 have a widespread alteration of the brain during development that manifests as one or more specific types of neuropsychologic deficits.
(AJDC. 1989;143:833-837)