Parkinson's disease (PD) is a movement disorder characterized by the selective degeneration of nigrostriatal dopaminergic neurons. Both familial and sporadic cases present tremor, rigidity, slowness ...of movement, and postural instability. Although major insights into the genes responsible for some rare hereditary cases have arisen, the etiology of sporadic cases remains unknown. Epidemiological studies have suggested an association with environmental toxins, mainly mitochondrial complex I inhibitors such as the widely used pesticide rotenone. In recent years, Drosophila melanogaster has been used as a model of several neurodegenerative diseases, including a genetic model of PD. Here, we studied the neurodegenerative and behavioral effects of a sublethal chronic exposure to rotenone in Drosophila. After several days, the treated flies presented characteristic locomotor impairments that increased with the dose of rotenone. Immunocytochemistry analysis demonstrated a dramatic and selective loss of dopaminergic neurons in all of the brain clusters. The addition of l-dopa (3,4-dihydroxy-L-phenylalanine) into the feeding medium rescued the behavioral deficits but not neuronal death, as is the case in human PD patients. In contrast, the antioxidant melatonin (N-acetyl-5-methoxytryptamine) alleviated both symptomatic impairment and neuronal loss, supporting the idea that this agent may be beneficial in the treatment of PD. Therefore, chronic exposure to pesticides recapitulates key aspects of PD in Drosophila and provides a new in vivo model for studying the mechanisms of dopaminergic neurodegeneration.
The catecholamines play a major role in the regulation of behavior. Here we investigate, in the fly Drosophila melanogaster, the role of dopamine and octopamine (the presumed arthropod homolog of ...norepinephrine) during the formation of appetitive and aversive olfactory memories. We find that for the formation of both types of memories, cAMP signaling is necessary and sufficient within the same subpopulation of mushroom-body intrinsic neurons. On the other hand, memory formation can be distinguished by the requirement for different catecholamines, dopamine for aversive and octopamine for appetitive conditioning. Our results suggest that in associative conditioning, different memories are formed of the same odor under different circumstances, and that they are linked to the respective motivational systems by their specific modulatory pathways.
Dopamine (DA) is a neurotransmitter with conserved behavioral roles between invertebrate and vertebrate animals. In addition to its neural functions, in insects DA is a critical substrate for cuticle ...pigmentation and hardening. Drosophila tyrosine hydroxylase (DTH) is the rate limiting enzyme for DA biosynthesis. Viable brain DA‐deficient flies were previously generated using tissue‐selective GAL4‐UAS binary expression rescue of a DTH null mutation and these flies show specific behavioral impairments. To circumvent the limitations of rescue via binary expression, here we achieve rescue utilizing genomically integrated mutant DTH. As expected, our DA‐deficient flies have no detectable DTH or DA in the brain, and show reduced locomotor activity. This deficit can be rescued by l‐DOPA/carbidopa feeding, similar to human Parkinson's disease treatment. Genetic rescue via GAL4/UAS‐DTH was also successful, although this required the generation of a new UAS‐DTH1 transgene devoid of most untranslated regions, as existing UAS‐DTH transgenes express in the brain without a Gal4 driver via endogenous regulatory elements. A surprising finding of our newly constructed UAS‐DTH1m is that it expresses DTH at an undetectable level when regulated by dopaminergic GAL4 drivers even when fully rescuing DA, indicating that DTH immunostaining is not necessarily a valid marker for DA expression. This finding necessitated optimizing DA immunohistochemistry, showing details of DA innervation to the mushroom body and the central complex. When DA rescue is limited to specific DA neurons, DA does not diffuse beyond the DTH‐expressing terminals, such that DA signaling can be limited to very specific brain regions.
Dopamine (DA) is an essential neurotransmitter regulating locomotor activity and reward in humans. The DA deficiency in humans manifests as Parkinson's disease (PD), a condition caused by death of dopaminergic neurons. Here, we develop a model of brain DA deficiency in fruit flies that allows rescue with genetic methods or using PD drugs. To adequately assess the effects of neuron‐selective rescue, we greatly improved upon DA immunohistochemistry detection to directly examine diffusion of release DA. With genetic rescue of DA synthesis limited to selected neurons innervating mushroom body and central complex, regions involved in regulating learning and locomotion, respectively, we found that DA does not diffuse to surrounding neurons, even with tightly intermingled neurons. This will allow precise manipulations in future studies. Furthermore, we show that tyrosine hydroxylase, the universally used marker of catecholamine neurons, is an imperfect marker of neuronal DA expression. Our new DA deficiency model will be useful in studying DA‐modulated neuronal pathways, and the compensatory signaling mechanisms that can modulate the course of PD.
Aim
Primary ciliary dyskinesia (PCD) is a rare (1:15 000) condition resulting in recurrent suppurative respiratory tract infections, progressive lung damage and hearing impairment. As the diagnosis ...is often delayed for years, the purpose of this study was to review the presenting features of children with PCD attending Australia's initial diagnostic PCD service over a 30‐year period.
Method
A retrospective review of the symptoms of children diagnosed with PCD at Concord Hospital between 1982 and 2012 was undertaken.
Results
One thousand thirty‐seven paediatric patients were referred for assessment and underwent nasal ciliary brushing. Eighty‐four (8.1%) had PCD based on microscopic analysis of nasal cilia. This included 81 with ciliary ultrastructural abnormalities demonstrated on electron microscopy and 3 with a suggestive phenotype, reduced ciliary beat frequency and a family history of PCD. The median age at diagnosis was 6.4 years (range 0.1 to 18.2 years). Forty‐six per cent had situs abnormalities and 31% had a family member with PCD. Recurrent cough (81%), rhinosinusitis (71%), recurrent otitis media (49%) and neonatal respiratory distress (57%) were reported. Bronchiectasis at presentation was documented in 32%. Situs abnormalities and neonatal respiratory distress were present together in 26%.
Conclusion
PCD remains under‐recognised by health‐care workers. The combination of neonatal respiratory distress, chronic suppurative cough and rhinosinusitis was the most common documented symptom cluster at presentation in cases of PCD. A heightened awareness of the clinical features of the disease may help to lower the age at diagnosis, facilitate appropriate treatment and improve long‐term outcomes.
Abstract In neurological disorders, both acute and chronic neural stress can disrupt cellular proteostasis, resulting in the generation of pathological protein. However in most cases, neurons adapt ...to these proteostatic perturbations by activating a range of cellular protective and repair responses, thus maintaining cell function. These interconnected adaptive mechanisms comprise a ‘proteostasis network’ and include the unfolded protein response, the ubiquitin proteasome system and autophagy. Interestingly, several recent studies have shown that these adaptive responses can be stimulated by preconditioning treatments, which confer resistance to a subsequent toxic challenge – the phenomenon known as hormesis. In this review we discuss the impact of adaptive stress responses stimulated in diverse human neuropathologies including Parkinson׳s disease, Wolfram syndrome, brain ischemia, and brain cancer. Further, we examine how these responses and the molecular pathways they recruit might be exploited for therapeutic gain. This article is part of a Special Issue entitled SI:ER stress.
The central theme of this study is Artin's braid group and the many ways that the notion of a braid has proved to be important in low-dimensional topology.
In Chapter 1 the author is concerned with ...the concept of a braid as a group of motions of points in a manifold. She studies structural and algebraic properties of the braid groups of two manifolds, and derives systems of defining relations for the braid groups of the plane and sphere. In Chapter 2 she focuses on the connections between the classical braid group and the classical knot problem. After reviewing basic results she proceeds to an exploration of some possible implications of the Garside and Markov theorems.
Chapter 3 offers discussion of matrix representations of the free group and of subgroups of the automorphism group of the free group. These ideas come to a focus in the difficult open question of whether Burau's matrix representation of the braid group is faithful. Chapter 4 is a broad view of recent results on the connections between braid groups and mapping class groups of surfaces. Chapter 5 contains a brief discussion of the theory of "plats." Research problems are included in an appendix.
L-glutamate is both the major brain excitatory neurotransmitter 1, 2 and a potent neurotoxin 3, 4 in mammals. Glutamate excitotoxicity is partly responsible for cerebral traumas evoked by ischemia 5, ...6 and has been implicated in several neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) 7–9. In contrast, very little is known about the function or potential toxicity of glutamate in the insect brain. Here, we show that decreasing glutamate buffering capacity is neurotoxic in Drosophila. We found that the only Drosophila high-affinity glutamate transporter, dEAAT1 10–13, is selectively addressed to glial extensions that project ubiquitously through the neuropil close to synaptic areas. Inactivation of dEAAT1 by RNA interference led to characteristic behavior deficits that were significantly rescued by expression of the human glutamate transporter hEAAT2 or the administration in food of riluzole, an anti-excitotoxic agent used in the clinic for human ALS patients. Signs of oxidative stress included hypersensitivity to the free radical generator paraquat and rescue by the antioxidant melatonin. Inactivation of dEAAT1 also resulted in shortened lifespan and marked brain neuropil degeneration characterized by widespread microvacuolization and swollen mitochondria. This suggests that the dEAAT1-deficient fly provides a powerful genetic model system for molecular analysis of glutamate-mediated neurodegeneration.
To compare the speech perception outcomes for patients with preoperative severe versus profound hearing loss with a cochlear implant (CI).
Retrospective patient review.
Cochlear implant program.
...Cochlear implant adult recipients (16 yr and above) having surgery between 2008 and 2015 with speech perception results and four frequency averaged severe (70-89 dBHL) or profound (90 dBHL and above) hearing loss. Prelingual deaf adults were included in the data.
Cochlear implant.
Speech perception scores with CUNY sentences and monosyllabic (CNC/CVC) word scores at preoperative and 3, 6, and 12 months postoperatively testing. Mann-Whitney U test was performed to compare outcomes of the two groups. Interquartile comparisons were also made.
The severe group had significantly better speech perception than the profound hearing loss group for CUNY sentences and CNC/CVC word scores preoperatively (p < 0.001) (p < 0.001), at 6 months (p < 0.001) (p < 0.001), and at 12 months (p < 0.01) (p < 0.001), respectively. At 3 months there was no significant difference. The number of patients in each severe or profound group at the different time points ranged from 92 to 367 patients for CUNY sentences and from 52 to 216 patients for the word scores. The 12 months' lower quartile score for CUNY sentences for severe and profound groups was 83% and 75% respectively. The lower quartile score for words was 32% and 26% respectively.
Adult CI recipients showed marked improvements in speech perception with a CI. Those with severe hearing loss have significantly better outcomes compared with profound hearing loss patients. These outcomes can inform CI candidacy evaluation criteria.
Alertness and behavioral performance depend on an animal’s level of arousal. In vertebrates, reinforcement and maintenance of arousal in the cortex are ensured by diffuse inputs from neurons ...releasing biogenic amine neuromodulators. Fruit flies similarly use dopamine for arousal control, indicating an ancient evolutionary origin of this essential feature of the functioning brain.
The primary aim was to analyze the speech perception outcomes of patients with cochlear implants 65 years and older, compared with those younger than 65 years. The secondary aim was to analyze if ...preoperative hearing levels, severe compared with profound, had an effect on speech perception outcomes in senior citizens.
Retrospective case review of 785 patients, between 2009 and 2016.
A large cochlear implant program.
Cochlear implant adult recipients younger than 65 years and 65 years and older at the time of surgery.
Therapeutic-cochlear implant.
Speech perception outcomes, using City University of New York (CUNY) sentences and Consonant-Nucleus-Consonant (CNC) words. Outcomes were measured preoperatively and postoperatively at 3, 6and 12 months for cohorts younger than 65 years and 65 years and older.
Adult recipients younger than 65 years compared with those 65 years and older had comparable outcomes for CUNY sentence scores outcomes ( p = 0.11) and CNC word scores ( p = 0.69). The preoperative four-frequency average severe hearing loss (HL) cohort was significantly better compared with the profound HL cohort, for both the CUNY sentence scores ( p < 0.001) and CNC word scores ( p < 0.0001). The four-frequency average severe HL cohort had better outcomes irrespective of age.
Senior citizens have similarly good speech perception outcomes as adults younger than 65 years. Those with preoperative severe HL have better outcomes than profound loss. These finds are reassuring and can be used when counseling older cochlear implant candidates.
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