High-Throughput Operant Conditioning in Drosophila Larvae

Operant conditioning is the process by which animals learn to associate their own behaviour with positive or negative outcomes, biasing future action selection in order to maximise reward and avoid punishment. It is an important strategy to ensure survival in an ever-changing environment. Although operant conditioning has been observed across vertebrate and invertebrate species, the underlying neural mechanisms are still not fully understood. The Drosophila larva is an excellent model system to study neural circuits, since it is genetically tractable, with a variety of tools available. Although it is quite small, it is capable of a diverse range of behaviours and can achieve complex learning tasks. However, while the mechanisms underlying classical conditioning, where animals learn about the appetitive or aversive qualities of an external sensory cue, have been extensively studied in larvae, it has remained an open question whether they are capable of operant conditioning. This is in part due to the challenges which arise during the training process: in order to train an animal to associate its own actions with their outcomes, the experimenter needs to be able to deliver rewarding or punishing stimuli directly in response to behaviour. In this thesis, I introduce a novel high-throughput tracker suitable for training up to 16 larvae simultaneously. I have developed a customised software for real-time detection of various actions that larvae perform: left and right bend, forward crawl, roll and back-up. Light and heat stimuli can be administered at individual animals with minimal delay, enabling optogenetic or thermogenetic activation of circuits encoding reward or punishment in response to behaviour. Using this system, I show that Drosophila larvae are capable of operant conditioning. Pairing bends to one direction, e.g. the left, with optogenetic activation of a large group of reward-encoding dopaminergic and serotonergic neurons is sufficient to induce a learned preference for bending towards this side after training. I explore whether there are other types of actions which larvae can learn to associate with valence, and introduce a second operant conditioning paradigm, in which larvae modify their behaviour following pairing of the stimulus with forward crawls. To identify new candidate neurons signalling valence in a learning context, I also conduct a classical conditioning screen, in which I pair an odour with optogenetic activation of distinct neuron types covered by different driver lines. While activation of many types of gustatory sensory neurons paired with the odour was insufficient for memory formation, I find that the serotonergic neurons of the brain and the subesophageal zone (SEZ) can induce strong appetitive learning. Finally, I show that activity of serotonergic rather than dopaminergic neurons is sufficient for memory formation in the operant bend direction paradigm, and that operant conditioning is impaired when restricting activation to the serotonergic neurons of the brain and the SEZ. My results suggest a novel role of serotonergic neurons for learning in insects as well as the existence of learning circuits outside of the mushroom body. Different subsets of serotonergic neurons mediate classical and operant conditioning. This works lays a foundation for future studies of the function of serotonin and the mechanisms underlying operant conditioning at both circuit level and cellular level.Gates Cambridge Scholarshi

Vibrational resonance, allostery, and activation in rhodopsin-like G protein-coupled receptors

G protein-coupled receptors are a large family of membrane proteins activated by a variety of structurally diverse ligands making them highly adaptable signaling molecules. Despite recent advances in the structural biology of this protein family, the mechanism by which ligands induce allosteric changes in protein structure and dynamics for its signaling function remains a mystery. Here, we propose the use of terahertz spectroscopy combined with molecular dynamics simulation and protein evolutionary network modeling to address the mechanism of activation by directly probing the concerted fluctuations of retinal ligand and transmembrane helices in rhodopsin. This approach allows us to examine the role of conformational heterogeneity in the selection and stabilization of specific signaling pathways in the photo-activation of the receptor. We demonstrate that ligand-induced shifts in the conformational equilibrium prompt vibrational resonances in the protein structure that link the dynamics of conserved interactions with fluctuations of the active-state ligand. The connection of vibrational modes creates an allosteric association of coupled fluctuations that forms a coherent signaling pathway from the receptor ligand-binding pocket to the G-protein activation region. Our evolutionary analysis of rhodopsin-like GPCRs suggest that specific allosteric sites play a pivotal role in activating structural fluctuations that allosterically modulate functional signals

Intra-urban vulnerability to heat-related mortality in New York City, 1997–2006

AbstractThe health impacts of exposure to summertime heat are a significant problem in New York City (NYC) and for many cities and are expected to increase with a warming climate. Most studies on heat-related mortality have examined risk factors at the municipal or regional scale and may have missed the intra-urban variation of vulnerability that might inform prevention strategies. We evaluated whether place-based characteristics (socioeconomic/demographic and health factors, as well as the built and biophysical environment) may be associated with greater risk of heat-related mortality for seniors during heat events in NYC. As a measure of relative vulnerability to heat, we used the natural cause mortality rate ratio among those aged 65 and over (MRR65+), comparing extremely hot days (maximum heat index 100°F+) to all warm season days, across 1997–2006 for NYC’s 59 Community Districts and 42 United Hospital Fund neighborhoods. Significant positive associations were found between the MRR65+ and neighborhood-level characteristics: poverty, poor housing conditions, lower rates of access to air-conditioning, impervious land cover, surface temperatures aggregated to the area-level, and seniors’ hypertension. Percent Black/African American and household poverty were strong negative predictors of seniors’ air conditioning access in multivariate regression analysis

New Developments in Virtual Reality-Assisted Treatment of Aggression in Forensic Settings:The Case of VRAPT

Aggression is a known problem in individuals being cared for in forensic settings, yet the evidence base for its treatment is scarce. Virtual Reality (VR) has been proposed as a promising addition to interventions in forensic settings, as it may increase the motivation among participants, bridge the gap between real life, therapeutic and laboratory experiences, and increase the ecological validity of psychological research. Recently, a new treatment for aggression using VR as the treatment environment, Virtual Reality Aggression Prevention Training (VRAPT) program, was developed to provide realistic and safe environments for participants to practice aggression management. In its current revised version, VRAPT is conceptualized as a form of cognitive behavioral therapy with its theoretical background in the General Aggression Model. Its purpose is to increase awareness of, and improve control over, one's own aggression and that of others through social interactions in individually tailored virtual environments. This manuscript describes how the lessons learned from the first randomized controlled trial of VRAPT have been applied to further develop the method and discusses challenges and future directions for VR-assisted treatment of aggression in forensic settings. VRAPT is a new psychological treatment for aggression and the coming years will provide expanded scientific evidence for further developments and adaptations

AMIRIS – Ein agentenbasiertes Strommarktmodell

Vorstellung von AMIRIS (Agentenbasiertes Modell zur Integration Regenerativer in den Strommarkt) im Rahmen des Workshops “Agentenbasierte Modellierung der Energiewende