Journal of neurogenetics最新文献

In Alzheimer's disease (AD), amyloid-β (Aβ) generation and upstream β-secretase 1 (BACE1) expression appear to be driven by oxidative stress via c-Jun N-terminal kinase (JNK), p38, and Interferon-Induced, Double-Stranded RNA-Activated Protein Kinase (PKR). In addition, inflammatory molecules, including lipopolysaccharide (LPS), induce genes central to Aβ genesis, such as BACE1, via nuclear factor-κB (NFκB). However, additional triggers of Aβ generation remain poorly understood and might represent novel opportunities for therapeutic intervention. Based on mechanistic studies and elevated ectopic oxidatively damaged DNA (oxoDNA) levels in preclinical AD, mild cognitive impairment, and AD patients, we hypothesize oxoDNA contributes to β-amyloidosis starting from the earliest stages of AD through multiple pathways. OxoDNA induces mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4), thereby sensitizing the brain to oxidative stress-induced JNK activation and BACE1 transcription. It also induces myeloid differentiation primary response 88 (MyD88) and activates protein kinase CK2, thereby increasing NFκB activation and BACE1 induction. OxoDNA increases oxidative stress via nuclear factor erythroid 2-related factor 2 (Nrf2) ectopic localization, likely augmenting JNK-mediated BACE1 induction. OxoDNA likely also promotes β-amyloidosis via absent in melanoma 2 (AIM2) induction. Falsifiable predictions of this hypothesis include that deoxyribonuclease treatment should decrease Aβ and possibly slow cognitive decline in AD patients. While formal testing of this hypothesis remains to be performed, a case report has found deoxyribonuclease I treatment improved a severely demented AD patient's Mini-Mental Status Exam score from 3 to 18 at 2 months. There is preliminary preclinical and clinical evidence suggesting that ectopic oxidatively damaged DNA may act as an inflammatory damage-associated molecular pattern contributing to Aβ generation in AD, and deoxyribonuclease I should be formally evaluated to test whether it can decrease Aβ levels and slow cognitive decline in AD patients.

Insects, as poikilotherms, have adaptations to deal with wide ranges in temperature fluctuation. Allelic variations in the foraging gene that encodes a cGMP dependent protein kinase, were discovered to have effects on behavior in Drosophila by Dr. Marla Sokolowski in 1980. This single gene has many pleiotropic effects and influences feeding behavior, metabolic storage, learning and memory and has been shown to affect stress tolerance. PKG regulation affects motoneuronal thermotolerance in Drosophila larvae as well as adults. While the focus of thermotolerance studies has been on the modulation of neuronal function, other cell types have been overlooked. Because glia are vital to neuronal function and survival, we wanted to determine if glia play a role in thermotolerance as well. In our investigation, we discovered a novel calcium wave at the larval NMJ and set out to characterize the wave's dynamics and the potential mechanism underlying the wave prior to determining what effect, if any, PKG modulation has on the thermotolerance of glia cells. Using pharmacology, we determined that calcium buffering mechanisms of the mitochondria and endoplasmic reticulum play a role in the propagation of our novel glial calcium wave. By coupling pharmacology with genetic manipulation using RNA interference (RNAi), we found that PKG modulation in glia alters thermoprotection of function as well as glial calcium wave dynamics.

Marla Sokolowski's scientific achievements established her as an internationally recognized leader in behavioural genetics. As a graduate student, she made a significant discovery while observing natural populations of the fruit fly, Drosophila melanogaster: the larvae exhibited a behavioural polymorphism which she traced to alleles of a single gene. Some larvae were 'sitters' which fed in a restricted location, while others were 'rovers' which ranged more widely in feeding. The gene in question, foraging, codes for a cyclic GMP kinase which is expressed in numerous locations throughout larval and adult Drosophila. Building on this foundation, she and her students have elucidated the genetic and environmental factors that account for individual differences in behaviour. In this article, I review significant stages of her scientific career.

The biogenic monoamine octopamine (OA) is a crucial regulator of invertebrate physiology and behavior. Since its discovery in the 1950s in octopus salivary glands, OA has been implicated in many biological processes among diverse invertebrate lineages. It can act as a neurotransmitter, neuromodulator and neurohormone in a variety of biological contexts, and can mediate processes including feeding, sleep, locomotion, flight, learning, memory, and aggression. Here, we focus on the roles of OA in female reproduction in insects. OA is produced in the octopaminergic neurons that innervate the female reproductive tract (RT). It exerts its effects by binding to receptors throughout the RT to generate tissue- and region-specific outcomes. OA signaling regulates oogenesis, ovulation, sperm storage, and reproductive behaviors in response to the female's internal state and external conditions. Mating profoundly changes a female's physiology and behavior. The female's OA signaling system interacts with, and is modified by, male molecules transferred during mating to elicit a subset of the post-mating changes. Since the role of OA in female reproduction is best characterized in the fruit fly Drosophila melanogaster, we focus our discussion on this species but include discussion of OA in other insect species whenever relevant. We conclude by proposing areas for future research to further the understanding of OA's involvement in female reproduction in insects.

The pursuit of understanding behavior has led to investigations of how genes, the environment, and the nervous system all work together to produce and influence behavior, giving rise to a field of research known as behavioral neurogenetics. This review focuses on the research journeys of two pioneers of aspects of behavioral neurogenetic research: Dr. Marla Sokolowski and Dr. Catharine Rankin as examples of how different approaches have been used to understand relationships between genes and behavior. Marla Sokolowski's research is centered around the discovery and analysis of foraging, a gene responsible for the natural behavioral polymorphism of Drosophila melanogaster larvae foraging behavior. Catharine Rankin's work began with demonstrating the ability to learn in Caenorhabditis elegans and then setting out to investigate the mechanisms underlying the "simplest" form of learning, habituation. Using these simple invertebrate organisms both investigators were able to perform in-depth dissections of behavior at genetic and molecular levels. By exploring their research and highlighting their findings we present ways their work has furthered our understanding of behavior and contributed to the field of behavioral neurogenetics.

The social ants, bees, wasps, and termites include some of the most ecologically-successful groups of animal species. Their dominance in most terrestrial environments is attributed to their social lifestyle, which enable their colonies to exploit environmental resources with remarkable efficiency. One key attribute of social insect colonies is the division of labour that emerges among the sterile workers, which represent the majority of colony members. Studies of the mechanisms that drive division of labour systems across diverse social species have provided fundamental insights into the developmental, physiological, molecular, and genomic processes that regulate sociality, and the possible genetic routes that may have led to its evolution from a solitary ancestor. Here we specifically discuss the conserved role of the foraging gene, which encodes a cGMP-dependent protein kinase (PKG). Originally identified as a behaviourally polymorphic gene that drives alternative foraging strategies in the fruit fly Drosophila melanogaster, changes in foraging expression and kinase activity were later shown to play a key role in the division of labour in diverse social insect species as well. In particular, foraging appears to regulate worker transitions between behavioural tasks and specific behavioural traits associated with morphological castes. Although the specific neuroethological role of foraging in the insect brain remains mostly unknown, studies in genetically tractable insect species indicate that PKG signalling plays a conserved role in the neuronal plasticity of sensory, cognitive and motor functions, which underlie behaviours relevant to division of labour, including appetitive learning, aggression, stress response, phototaxis, and the response to pheromones.

Marla Sokolowski's work and humanity has influenced the careers of hundreds, perhaps thousands, of younger scientists. Her fundamental research on the neurogenetic underpinnings of behavior in Drosophila melanogaster is remarkable not only for its scientific brilliance, but for the humility, care, and humor with which it was conducted.

Hypersynchronous neural activity is a characteristic feature of seizures. Although many Drosophila mutants of epilepsy-related genes display clear behavioral spasms and motor unit hyperexcitability, field potential measurements of aberrant hypersynchronous activity across brain regions during seizures have yet to be described. Here, we report a straightforward method to observe local field potentials (LFPs) from the Drosophila brain to monitor ensemble neural activity during seizures in behaving tethered flies. High frequency stimulation across the brain reliably triggers a stereotypic sequence of electroconvulsive seizure (ECS) spike discharges readily detectable in the dorsal longitudinal muscle (DLM) and coupled with behavioral spasms. During seizure episodes, the LFP signal displayed characteristic large-amplitude oscillations with a stereotypic temporal correlation to DLM flight muscle spiking. ECS-related LFP events were clearly distinct from rest- and flight-associated LFP patterns. We further characterized the LFP activity during different types of seizures originating from genetic and pharmacological manipulations. In the 'bang-sensitive' sodium channel mutant bangsenseless (bss), the LFP pattern was prolonged, and the temporal correlation between LFP oscillations and DLM discharges was altered. Following administration of the pro-convulsant GABA_A blocker picrotoxin, we uncovered a qualitatively different LFP activity pattern, which consisted of a slow (1-Hz), repetitive, waveform, closely coupled with DLM bursting and behavioral spasms. Our approach to record brain LFPs presents an initial framework for electrophysiological analysis of the complex brain-wide activity patterns in the large collection of Drosophila excitability mutants.