Biology subjects

Kottler, B.

Publications and source records attributed to Kottler, B..

5 recordsLinked to original sources

bioRxiv2020

Presynaptic accumulation of α-synuclein causes synaptopathy and progressive neurodegeneration

Alpha-synuclein (-syn) mislocalisation and accumulation in intracellular inclusions is the major pathological hallmark of degenerative synucleinopathies, including Parkinsons disease, Parkinsons disease with Dementia and Dementia with Lewy Bodies. Typical symptoms are behavioural abnormalities including motor deficits that mark disease progression, while non-motor symptoms and synaptic deficits are already apparent during the early stages of disease. Synucleinopathies have therefore been considered synaptopathies that exhibit synaptic dysfunction prior to neurodegeneration. However, the mechanisms and events underlying synaptopathy are largely unknown. Here we investigated the cascade of pathological events underlying -syn accumulation and toxicity in a Drosophila model of synucleinopathy by employing a combination of histological, biochemical, behavioural and electrophysiological assays. Our findings demonstrate that targeted expression of human -syn leads to its accumulation in presynaptic terminals that caused downregulation of synaptic proteins, Cysteine String Protein, Synapsin, and Syntaxin 1A, and a reduction in the number of Bruchpilot puncta, the core component of the presynaptic active zone essential for its structural integrity and function. These -syn-mediated presynaptic alterations resulted in impaired neuronal function, which triggered behavioural deficits in ageing Drosophila that occurred prior to progressive degeneration of dopaminergic neurons. Comparable alterations in presynaptic active zone protein were found in patient brain samples of Dementia with Lewy Bodies. Together, these findings demonstrate that presynaptic accumulation of -syn impairs the active zone and neuronal function, which together cause synaptopathy that results in behavioural deficits and the progressive loss of dopaminergic neurons. This sequence of events resembles the cytological and behavioural phenotypes that characterise the onset and progression of synucleinopathies, suggesting that -syn mediated synaptopathy is an initiating cause of age-related neurodegeneration.

neuroscience↗

bioRxiv2019

Ancestral regulatory mechanisms specify conserved midbrain circuitry in arthropods and vertebrates

Corresponding attributes of neural development and function suggest arthropod and vertebrate brains may have an evolutionarily conserved organization. However, the underlying mechanisms have remained elusive. Here we identify a gene regulatory and character identity network defining the deutocerebral-tritocerebral boundary (DTB) in Drosophila. We show this network comprises genes homologous to those directing midbrain-hindbrain boundary (MHB) formation in vertebrates and their closest chordate relatives. Genetic tracing reveals that the embryonic DTB gives rise to adult midbrain circuits that in flies control auditory and vestibular information processing and motor coordination, as do MHB-derived circuits in vertebrates. DTB-specific gene expression and function is directed by cis-regulatory elements (CREs) of developmental control genes that include homologs of mammalian Zinc finger of the cerebellum and Purkinje cell protein 4. Moreover, Drosophila DTB-specific CREs correspond to regulatory sequences of human ENGRAILED-2, PAX-2 and DACHSHUND-1 that direct MHB-specific expression in the embryonic mouse brain. Together, these findings imply ancestral regulatory mechanisms mediating the genetic specification of midbrain-cerebellar circuitry for balance and motor control that may predated the radiation of cephalic nervous systems across the animal kingdom.

neuroscience↗

bioRxiv2019

Drosophila insulin-like peptide 2 mediates dietary regulation of sleep intensity

Sleep is a nearly universal behavior that is regulated by diverse environmental and physiological stimuli. A defining feature of sleep is a homeostatic rebound following deprivation, where animals compensate for lost sleep by increasing sleep duration and/or sleep depth. Fruit flies exhibit robust recovery sleep following deprivation and represent a powerful model to study neural circuits regulating sleep homeostasis. Numerous neuronal populations have been identified in modulating sleep homeostasis as well as depth, raising the possibility that recovery sleep is differentially regulated by environmental or physiological processes that induce sleep deprivation. Here, we find that unlike most pharmacological and environmental manipulations commonly used to restrict sleep, starvation potently induces sleep loss without a subsequent rebound in sleep duration or depth. We find that both starvation and a sucrose-only diet result in reduced metabolic rate and increased sleep depth, suggesting that dietary yeast protein is essential for normal sleep depth and homeostasis. Finally, we find that Drosophila insulin like peptide 2 (Dilp2) is required for starvation-induced changes in sleep depth without regulating the duration of sleep. Remarkably, Dilp2 mutant flies require rebound sleep following sleep deprivation, suggesting Dilp2 underlies resilience to sleep loss. Together, these findings reveal innate resilience to starvation-induced sleep loss and identify distinct mechanisms that underlie starvation-induced changes in sleep duration and depth.\n\nAuthor SummarySleep is nearly universal throughout the animal kingdom and homeostatic regulation represents a defining feature of sleep, where animals compensate for lost sleep by increasing sleep over subsequent time periods. Despite the robustness of this feature, surprisingly little is known about how recovery-sleep is regulated in response to different types of sleep deprivation. Fruit flies provide a powerful model for investigating the genetic regulation of sleep, and like mammals, display robust recovery sleep following deprivation. Here, we find that unlike most stimuli that suppress sleep, sleep deprivation by starvation does not require a homeostatic rebound. These findings appear to be due to flies engaging in deeper sleep during the period of partial deprivation, suggesting a natural resilience to starvation-induced sleep loss. This unique resilience to starvation-induced sleep loss is dependent on Drosophila insulin-like peptide 2, suggesting a critical role for insulin signaling in regulating interactions between diet and sleep homeostasis.

neuroscience↗

bioRxiv2018

Dopamine D1 receptor signalling differentially regulates action sequences and turning behaviour in freely moving Drosophila

Here, we introduce a novel behavioural paradigm to study neural circuits and mechanisms underlying action selection and decision-making in freely moving Drosophila. We first validate our approach by studying FoxP mutants and show that normally invariant patterns of motor activity and turning behaviour are altered in these flies, reminiscent of indecision. Then, focusing on central complex (CX) circuits known to integrate different sensory modalities and controlling premotor regions, we show that action sequences and turning behaviour are regulated by dopamine D1 (Dop1R1) receptor signalling. Dop1R1 inputs onto CX columnar wedge and ellipsoid body R2/R4m ring neuron circuits both negatively gate motor activity but inversely control turning behaviour. While flies deficient of D1 receptor signalling present normal turning behaviour despite decreased activity, restoring Dop1R1 level in R2/R4m-specific circuitry affects the temporal organisation of motor actions and turning. These findings suggest that columnar wedge and ring neuron circuits of the CX differentially modulate patterns of motor action sequences and turning behaviour by comparative Dop1R1 signalling for goal-directed locomotion.

neuroscience↗

bioRxiv2017

A lineage-related reciprocal inhibition circuitry for sensory-motor action selection

The insect central complex and vertebrate basal ganglia are forebrain centres involved in selection and maintenance of behavioural actions. However, little is known about the formation of the underlying circuits, or how they integrate sensory information for motor actions. Here, we show that paired embryonic neuroblasts generate central complex ring neurons that mediate sensory-motor transformation and action selection in Drosophila. Lineage analysis resolves four ring neuron subtypes, R1-R4, that form GABAergic inhibition circuitry among inhibitory sister cells. Genetic manipulations, together with functional imaging, demonstrate subtype-specific R neurons mediate the selection and maintenance of behavioural activity. A computational model substantiates genetic and behavioural observations suggesting that R neuron circuitry functions as salience detector using competitive inhibition to amplify, maintain or switch between activity states. The resultant gating mechanism translates facilitation, inhibition and disinhibition of behavioural activity as R neuron functions into selection of motor actions and their organisation into action sequences.

neuroscience↗