Faculty Bibliography

Labile memory is thought to be held in the brain as persistent neural network activity. However, it is not known how biologically relevant memory circuits are organized and operate. Labile and persistent appetitive memory in Drosophila requires output after training from the α'β' subset of mushroom body (MB) neurons and from a pair of modulatory dorsal paired medial (DPM) neurons. DPM neurons innervate the entire MB lobe region and appear to be pre- and postsynaptic to the MB, consistent with a recurrent network model. Here we identify a role after training for synaptic output from the GABAergic anterior paired lateral (APL) neurons. Blocking synaptic output from APL neurons after training disrupts labile memory but does not affect long-term memory. APL neurons contact DPM neurons most densely in the α'β' lobes, although their processes are intertwined and contact throughout all of the lobes. Furthermore, APL contacts MB neurons in the α' lobe but makes little direct contact with those in the distal α lobe. We propose that APL neurons provide widespread inhibition to stabilize and maintain synaptic specificity of a labile memory trace in a recurrent DPM and MB α'β' neuron circuit.

Taste is an early stage in food and drink selection for most animals [1, 2]. Detecting sweetness indicates the presence of sugar and possible caloric content. However, sweet taste can be an unreliable predictor of nutrient value because some sugars cannot be metabolized. In addition, discrete sugars are detected by the same sensory neurons in the mammalian [3] and insect [4, 5] gustatory systems, making it difficult for animals to readily distinguish the identity of different sugars using taste alone [6-8]. Here we used an appetitive memory assay in Drosophila [9-11] to investigate the contribution of palatability and relative nutritional value of sugars to memory formation. We show that palatability and nutrient value both contribute to reinforcement of appetitive memory. Nonnutritious sugars formed less robust memory that could be augmented by supplementing with a tasteless but nutritious substance. Nutrient information is conveyed to the brain within minutes of training, when it can be used to guide expression of a sugar-preference memory. Therefore, flies can rapidly learn to discriminate between sugars using a postingestive reward evaluation system, and they preferentially remember nutritious sugars.

The purpose of this is case-based review is to report a series of patients with rheumatoid arthritis who developed stridor and highlight this potentially life-threatening manifestation of the disease. We report three cases from the Rheumatology Department of University College Hospital, London and review the literature on the prevalence, clinical presentation, histopathological features and treatment of laryngeal involvement in rheumatoid arthritis. In two patients, emergency tracheostomy was necessary to maintain a patent airway. One patient improved with systemic corticosteroids without the need for surgical intervention. All patients were seropositive with anti-CCP antibodies and had long-standing erosive disease. Stridor in patients with rheumatoid arthritis is typically due to arthritis of the cricoarytenoid joints leading to fixation of the vocal cords in a midline position. Cricoarytenoid joint arthritis may be acute, chronic, or acute-on-chronic. Emergency tracheostomy may be life-saving in cases of acute stridor. Cricoarytenoid inflammation and airway compromise may respond to local or systemic corticosteroid therapy. Other causes of vocal cord paresis in rheumatoid arthritis include ischaemic neuropathy of the recurrent laryngeal and vagus nerves due to vasculitis or cervicomedullary compression due to rheumatoid involvement of the cervical spine.

Ultrasound-guided wire localization of impalpable lesions is a well-recognized technique in the management of breast pathology, but its use in the head and neck is not well described. Performed under local anesthesia, high-resolution ultrasound provides real-time imaging for accurate placement of the wire resulting in fewer complications. Wire localization can focus the surgical approach, which reduces operating time and minimizes trauma to surrounding tissues. In this technical note, we describe two cases of pre-operative ultrasound-guided wire localization to facilitate the surgical excision of impalpable neck lesions.

Melanoma is a tumour of transformed melanocytes, which are originally derived from the embryonic neural crest. It is unknown to what extent the programs that regulate neural crest development interact with mutations in the BRAF oncogene, which is the most commonly mutated gene in human melanoma. We have used zebrafish embryos to identify the initiating transcriptional events that occur on activation of human BRAF(V600E) (which encodes an amino acid substitution mutant of BRAF) in the neural crest lineage. Zebrafish embryos that are transgenic for mitfa:BRAF(V600E) and lack p53 (also known as tp53) have a gene signature that is enriched for markers of multipotent neural crest cells, and neural crest progenitors from these embryos fail to terminally differentiate. To determine whether these early transcriptional events are important for melanoma pathogenesis, we performed a chemical genetic screen to identify small-molecule suppressors of the neural crest lineage, which were then tested for their effects on melanoma. One class of compound, inhibitors of dihydroorotate dehydrogenase (DHODH), for example leflunomide, led to an almost complete abrogation of neural crest development in zebrafish and to a reduction in the self-renewal of mammalian neural crest stem cells. Leflunomide exerts these effects by inhibiting the transcriptional elongation of genes that are required for neural crest development and melanoma growth. When used alone or in combination with a specific inhibitor of the BRAF(V600E) oncogene, DHODH inhibition led to a marked decrease in melanoma growth both in vitro and in mouse xenograft studies. Taken together, these studies highlight developmental pathways in neural crest cells that have a direct bearing on melanoma formation.

The most common mutation in human melanoma, BRAF(V600E), activates the serine/threonine kinase BRAF and causes excessive activity in the mitogen-activated protein kinase pathway. BRAF(V600E) mutations are also present in benign melanocytic naevi, highlighting the importance of additional genetic alterations in the genesis of malignant tumours. Such changes include recurrent copy number variations that result in the amplification of oncogenes. For certain amplifications, the large number of genes in the interval has precluded an understanding of the cooperating oncogenic events. Here we have used a zebrafish melanoma model to test genes in a recurrently amplified region of chromosome 1 for the ability to cooperate with BRAF(V600E) and accelerate melanoma. SETDB1, an enzyme that methylates histone H3 on lysine 9 (H3K9), was found to accelerate melanoma formation significantly in zebrafish. Chromatin immunoprecipitation coupled with massively parallel DNA sequencing and gene expression analyses uncovered genes, including HOX genes, that are transcriptionally dysregulated in response to increased levels of SETDB1. Our studies establish SETDB1 as an oncogene in melanoma and underscore the role of chromatin factors in regulating tumorigenesis.

Probability and risk are important factors for value-based decision making and optimal foraging. In order to survive in an unpredictable world, organisms must be able to assess the probability and risk attached to future events and use this information to generate adaptive behavior. Recent studies in non-human primates and rats have shown that both probability and risk are processed in a distributed fashion throughout the brain at the level of single neurons. Reward probability has mainly been shown to be coded by phasic increases and decreases in firing rates in neurons in the basal ganglia, midbrain, parietal, and frontal cortex. Reward variance is represented in orbitofrontal and posterior cingulate cortex and through a sustained response of dopaminergic midbrain neurons.

This article reviews the role of imaging in the management of trauma patients. First the trauma series is reviewed, principally the chest, pelvis and cervical spine radiographs along with an approach to their interpretation. The role of computed tomography in trauma imaging is then discussed.

The importance of cranial computed tomography in the diagnosis and follow up of intracranial pathology cannot be underestimated. Clinicians at every level should have a basic understanding of this technique. This second part discusses the practical use of computed tomography in the clinical setting.

Individuals can learn by interacting with the environment and experiencing a difference between predicted and obtained outcomes (prediction error). However, many species also learn by observing the actions and outcomes of others. In contrast to individual learning, observational learning cannot be based on directly experienced outcome prediction errors. Accordingly, the behavioral and neural mechanisms of learning through observation remain elusive. Here we propose that human observational learning can be explained by two previously uncharacterized forms of prediction error, observational action prediction errors (the actual minus the predicted choice of others) and observational outcome prediction errors (the actual minus predicted outcome received by others). In a functional MRI experiment, we found that brain activity in the dorsolateral prefrontal cortex and the ventromedial prefrontal cortex respectively corresponded to these two distinct observational learning signals.