skip to primary navigationskip to content

Wolfson-PDN studentship projects 2021

Supervisor

Project

Riccardo Beltramo

ric.beltramo@gmail.com

 

Relevant references:

  • Beltramo R. & Scanziani M. A collicular visual cortex: Neocortical space for an ancient midbrain visual structure. Science, 2019 Jan 4;363(6422):64-69. https://doi.org/10.1126/science.aau7052
  • Beltramo R. A new primary visual cortex. Science, 2020 Oct 2;370(6512):46. https://doi.org/10.1126/science.abe1482
  • LaChance P.A., Todd T.P. & Taube, J.S. A sense of space in postrhinal cortex. Science, 2019 Jul 12;365(6449), eaax4192 https://doi.org/10.1126/science.aax4192

 

The roles of modern and ancestral visual pathways, for defensive behaviors and spatial navigation

Our brain is the result of a long evolution. Over time, new brain regions superseded functions originally performed by preexisting areas. Newer structures did not merely replace older ones but rather integrated with them, increasing circuit complexity. What roles ancient and modern, functionally similar brain regions play in behavior?

The visual system offers an ideal model for studying this question. Mammals have two coexisting brain structures that process visual information: the ancient “superior colliculus” and the phylogenetically newer “visual cortex”. This PhD project aims to determine the roles of these parallel visual systems in two natural behaviors crucial for survival: innate defensive responses and spatial navigation.

Visually-evoked innate defensive behaviors, such as freezing upon detection of distant predators, critically reduce the probability of being eaten. Equally essential for survival is the ability to adroitly navigate the environment, creating internal spatial maps of the world based on visual landmarks and optic flow. We have recently discovered that the superior colliculus has a dedicated space in the visual cortex: the postrhinal area (POR) (Beltramo & Scanziani,2019; Beltramo,2020). POR, whose responses rely on collicular activity and are critically involved in spatial navigation (LaChance et al.,2019), is perfectly placed at the interface between the cortical and collicular visual streams. This system provides us with a unique model to study the interactions between ancient and modern neural pathways in visual information processing.

Combining electrophysiological, 2photon imaging, and opto/chemogenetic approaches, we will study how evolutionarily old and recent visual systems interact to generate complex behaviors essential for survival.

Riccardo Beltramo

ric.beltramo@gmail.com

 

Relevant references:

  • 1) Dunsmoor J. & Paz R. Fear Generalization and Anxiety: Behavioral and Neural Mechanisms. Biol Psychiatry, 2015 Sep 1;78(5):336-43. https://doi.org/10.1016/j.biopsych.2015.04.010
  • 2) Beltramo R. & Scanziani M. A collicular visual cortex: Neocortical space for an ancient midbrain visual structure. Science, 2019 Jan 4;363(6422):64-69. https://doi.org/10.1126/science.aau7052
  • 3) Burgess C.R., Rohan N. Ramesh R.N., Sugden A.U., Levandowski K.M., Minnig M.A., Fenselau H., Lowell B.B, Andermann M.L. Hunger-dependent enhancement of food cue responses in mouse postrhinal cortex and lateral amygdala. Neuron, 2016 Sep 7; 91(5):1154–1169. https://doi.org/10.1016/j.neuron.2016.07.032

 

Sensory processing and fear overgeneralization in stress-induced anxiety, across the visual system

Anxiety disorders stem from dysfunctions in the circuits that process aversive stimuli (1). When confronted with potential dangers, animals must select the appropriate behavioral response. In an environment full of complex stimuli, sometimes threat cues are ambiguous, making it challenging to distinguish dangerous from irrelevant stimuli. The ability to generalize across similar stimuli is an adaptive strategy that protects animals from fatally missing a potentially deadly environmental cue. In other words, “better safe than sorry”. However, an exaggerated generalization of fear to harmless stimuli (i.e. “fear overgeneralization”) is maladaptive and considered a hallmark of numerous anxiety disorders.

The cellular and circuit mechanisms mediating fear overgeneralization are largely unknown. This PhD project investigates the development of fear overgeneralization at the level of the sensory circuits that process aversive information.

Using the mouse visual system as a model, we will focus on a visual cortex selectively activated by innately fearful stimuli (2), targeted by the amygdala (3), and driven by a midbrain center that triggers avoidance behaviors. We will determine how changes in the neural sensory representations of dangerous and safe visual stimuli affect the animals’ ability to discriminate them. Given the critical role of preexisting stress in the pathogenesis of numerous anxiety disorders, we will test the hypothesis that emotional distress changes how sensory stimuli are encoded during learning, leading to fear overgeneralization. Through chronic 2photon imaging, large-scale electrophysiology, and innovative behavioral tasks, we will determine the effects of severe stressors on early sensory processing, during the development of stress-induced anxiety.

Elisa Galliano

 

Relevant references:

  • [1] M. Morales and E. B. Margolis, ‘Ventral tegmental area: cellular heterogeneity, connectivity and behaviour’, Nat. Rev. Neurosci., vol. 18, no. 2, pp. 73–85, 2017.
  • [2] E. Galliano et al., ‘Embryonic and postnatal neurogenesis produce functionally distinct subclasses of dopaminergic neuron’, eLife, vol. 7, Apr. 2018.
  • [3] S. Jones and A. Bonci, ‘Synaptic plasticity and drug addiction’, Curr. Opin. Pharmacol., vol. 5, no. 1, pp. 20–25, Feb. 2005.

Heterogeneity and plasticity of dopaminergic neurons

In the mammalian brain, the majority of dopaminergic neurons reside in the midbrain (Substantia Nigra pars compacta, and the Ventral Tegmental Area), the olfactory bulb and the diencephalon. Midbrain DA neurons exhibit different protein expression, neurotransmitter co-release and projection target pattern[1]. In the olfactory bulb, dopaminergic neurons are found to exist in two subclasses, in a process known as adult neurogenesis[2]. Given the heterogeneity of dopaminergic neurons within and across brain regions, can a given population of dopamine neurons substitute for another, for example in transplant studies? Or are different dopaminergic neuron populations functionally completely distinct?

The first goal of this project will be to use whole-cell patch clamp recording in acute brain slices from transgenic mice to electrophysiologically profile the different populations of dopaminergic neurons, and to determine whether heterogeneity in dopaminergic neurons within each brain region is related to morphology and/or synaptic connectivity.

The second goal of this project is to study how different activity-dependent plastic changes (synaptic, intrinsic, structural) occur in each dopaminergic population. Initially activity-dependent plasticity will be induced optogenetically in acute brain slices, and plasticity assessed electrophysiologically and morphologically. We will then move in vivo  by inducing plasticity with behaviourally relevant paradigms, such as olfactory deprivation/enrichment, and the systemic delivery of drugs of abuse that cause neuronal and behavioural plasticity in midbrain dopamine reward pathways[3].

Elisa Galliano

 

Relevant references:

  • [1] P.-M. Lledo, M. Alonso, and M. S. Grubb, ‘Adult neurogenesis and functional plasticity in neuronal circuits’, Nat. Rev. Neurosci., vol. 7, no. 3, pp. 179–193, Mar. 2006, doi: 10.1038/nrn1867.
  • [2] E. Galliano et al., ‘Embryonic and postnatal neurogenesis produce functionally distinct subclasses of dopaminergic neuron’, eLife, vol. 7, Apr. 2018, doi: 10.7554/eLife.32373.
  • [3] E. Galliano, C. Hahn, L. Browne, P. R. Villamayor, and M. S. Grubb, ‘Brief sensory deprivation triggers cell type-specific structural and functional plasticity in olfactory bulb neurons’, bioRxiv, p. 2020.05.10.086926, Jan. 2020, doi: 10.1101/2020.05.10.086926.

Plasticity and adult neurogenesis in the olfactory circuit

A crucial aspect of brain development and function is that neurons can structurally and functionally modify themselves and the strength of their connections with other neurons in response to certain stimulus patterns. These changes pertain to three main classes of plasticity: synaptic intrinsic, and structural. In the olfactory circuit, structural plasticity is taken to an extreme: not only neurons can change size and shape of cellular sub-compartments, but quite a few neuronal subpopulations can regenerate throughout life, adding and removing entire elements of the circuit [1]. Among these regenerating cells are olfactory sensory neurons in the nasal epithelium, dopaminergic cells and granule cells in the olfactory bulb, and interneurons in the olfactory cortex. While adult-born neurons have long been believed to be a like-for-like replacement of embryonic-born ones, recent work focusing on bulbar dopaminergic neurons has challenged this view. Indeed, embryonic and postnatally-born bulbar dopaminergic cells differ in morphology, function and activity-dependent plasticity [2-3]. Using transgenic mouse models, immunohistochemistry, electrophysiology, and behavioural testing, this project wants to expand on these findings. Specifically it wishes to investigate (a) whether the differences based on birth date seen in the dopaminergic population can be generalized to the other regenerating populations in the olfactory system, and (b) what behavioural roles do embryonic and regenerating cells play in olfactory processing.

Dino A. Giussani

 

Relevant references:

  • Giussani, D.A. (2016). The Fetal Brain Sparing Response to Hypoxia: Physiological Mechanisms.  The Journal of Physiology 594(5), 1215-30.

 

Arterial chemoreflex function in fetal life

After birth, arterial chemoreceptors primarily function to regulate respiratory activity.  In contrast, we have discovered that in fetal life, arterial chemoreceptors primarily function to regulate cardiovascular defences to reductions in fetal oxygenation. 

A fall in fetal oxygenation or acute hypoxia is a common challenge in pregnancy, for instance during compression of the umbilical cord.  In response to hypoxia, the carotid body in the fetus triggers a neural reflex, which reduces fetal heart rate and redistributes the fetal cardiac output away from peripheral circulations and towards the fetal brain.  The reduction in fetal heart rate reduces oxygen consumption by the fetal heart.  The redistribution of blood flow protects the fetal brain against hypoxia – the so called fetal brain sparing effect.

We have delineated the neural pathways of this carotid chemoreflex, as well as receptor and signalling mechanisms. However, it remains completely unknown how the carotid body matures with advancing gestation and underlying mechanisms mediating this maturation.

In fetal life, there is an increase in fetal plasma cortisol with advancing gestation towards term.  This exponential increase in fetal cortisol interacts with thyroid hormones and is responsible for maturing a number of systems in preparation to sustain postnatal life, most famously the fetal lung.  However, the role of fetal cortisol or thyroid hormones in maturing the fetal carotid chemoreflex is unknown.

This PhD will use an established sheep model of fetal physiology to determine the role of fetal cortisol and thyroid hormones in maturing chemoreflex function in fetal life.  The research will involve fetal surgery and experiments in chronically instrumented fetal sheep.

Allan Herbison

aeh36@cam.ac.uk

 

Relevant references:

  • Herbison AE (2016) Control of puberty onset and fertility by gonadotropin-releasing hormone neurons. Nature Rev Endo, 12, 452-466.
  • Clarkson J, Han SY, Piet R, McLennan T, Kane G, Ng J, Porteous R, Kim J, Colledge WH, Iremonger KJ, Herbison AE (2017) Definition of the hypothalamic GnRH pulse generator in mice. Proc Natl Acad Sci (USA) 114, E10216-E10223.

Understanding neural circuit dysfunction in polycystic ovary syndrome (PCOS)

Approximately one in five women in the UK suffer from polycystic ovary syndrome (PCOS) a condition typified by problems with fertility, high androgen levels, and altered metabolism.  Accruing clinical and biomedical evidence indicate that over-activity of the hypothalamic gonadotropin-releasing hormone (GnRH) pulse generator has a major role in generating the sub-fertility of women with PCOS. The GnRH pulse generator is responsible for driving the pulsatile release of reproductive hormones that control ovarian function (Herbison, Nature Endo Revs 2016). Studies involving the real-time imaging of neural activity in genetic mouse models have revealed that a population of kisspeptin neurons located in the arcuate nucleus (ARN) of the hypothalamus is the long-sought “GnRH pulse generator” (Clarkson et al., PNAS, 114, 2017).

This project aims to characterise the activity of the ARN kisspeptin neurons in a well-established mouse model of PCOS. Female embryos exposed to high levels of androgen in utero develop a PCOS phenotype with abnormally fast GnRH pulses and disordered fertility. The candidate will use adeno-associated viruses in Kiss1-Cre transgenic mouse lines to express the calcium indicator GCaMP selectively in ARN kisspeptin neurons. The on-going activity of this population of cells will then be measured using GCaMP fibre photometry in conscious freely-behaving mice to assess the characteristics of the pulse generator in PCOS mice. Subsequent studies will undertake single-cell RNAseq analyses of differential gene expression in ARN kisspeptin neurons from normal and PCOS mice. Finally, the candidate will examine the effects on GnRH pulse generation and fertility of modulating selected genes specifically in ARN kisspeptin neurons using in vivo CRISPR gene editing.

Julija Krupic

www.krupiclab.com

 

Relevant references:

  • Banino et al 2018 Nature
  • Jun, Bauza et al 2018 Nature
  • Krupic, Bauza et al 2018 Science

 

Building a biologically inspired spatial cognitive map in artificial agents

The main aim of this project is to construct biologically inspired AI neural networks for building spatial representations of newly encountered environments. The longer term goal is to apply these artificial systems for designing efficient self-navigating agents (e.g. self-driving cars, robots etc) as well as to potentially provide valuable insights into how the underlying principles of the computations performed by the hippocampal-parahippocampal network itself. Our lab in collaboration with Dr Marius Bauza (UCL) has recently simultaneously recorded the activity of multiple hippocampal-parahippocampal cells (place cells, grid cells, border cells etc) using high density Neuropixels probes as an animal performed three-hour-long continuous exploration (foraging for randomly scattered food) of a novel enclosure. Such a long trial for the first time allowed us to quantify the real-time dynamics of the hippocampal-cognitive map during the continuous learning. We believe that this data will inform the design of machine learning agents mimicking the hippocampal neural activity.

Julija Krupic

www.krupiclab.com

 

Relevant references:

  • Guerreiro, R., Bras, J., 2015. The age factor in Alzheimer’s disease. Genome Med. 7. https://doi.org/10.1186/s13073-015-0232-5

  • Nilsson, L.-G., Adolfsson, R., Bäckman, L., Frias, C.M. de, Molander, B., Nyberg, L., 2004. Betula: A Prospective Cohort Study on Memory, Health and Aging. Aging Neuropsychol. Cogn. 11, 134–148. https://doi.org/10.1080/13825580490511026

  • Nilsson, L.-Gör., BÄCkman, L., Erngrund, K., Nyberg, L., Adolfsson, R., Bucht, Gös., Karlsson, S., Widing, M., Winblad, B., 1997. The betula prospective cohort study: Memory, health, and aging. Aging Neuropsychol. Cogn. 4, 1–32. https://doi.org/10.1080/13825589708256633

Developing smart mobile App for continuous life-long monitoring of cognitive performance and its application for pre-clinical detection of prodromal Alzheimer's disease

It has been well established that age is the largest risk factor for sporadic Alzheimer’s disease (AD)(Guerreiro and Bras, 2015; Nilsson et al., 2004, 1997) and currently it is unknown what triggers the disease and how it progresses. Hence, there is an urgent need to develop real-time longitudinal phenotyping systems for assessing AD-related cognitive performance such as episodic and spatial memory. Moreover, in order to understand the underlying mechanisms of the disease and identify effective intervention methods it is crucial that the system used is directly comparable to phenotyping used in AD animal research. The aims of this project are to develop a game-like interactive smartphone app for continuous longitudinal testing of cognitive performance in humans and to test the app in healthy individuals and MCI patients. The results will be compared with the analogous testing platform for rodents developed by the Krupic Lab.

Ole Paulsen

 

Relevant references:

  • Bouvier G, Larsen RS, Rodriguez Moreno A, Paulsen O and Sjöström PJ (2018) Towards resolving the presynaptic NMDA receptor debate. Curr Opin Neurobiol 51: 1–7.
  • Gonzalez-Rueda A, Feord R, Pedrosa V, Clopath C, Paulsen O (2018) Activity-dependent downscaling of subthreshold synaptic inputs during slow wave sleep-like activity in vivo. Neuron 97: 1244-1252.
  • Rodriguez-Moreno A and Paulsen O (2008) Spike timing-dependent long-term depression requires presynaptic NMDA receptors. Nat Neurosci 11: 744-745.

 

Presynaptic NMDA receptors in long-term synaptic plasticity

N-methyl-D-aspartate receptors (NMDARs) are necessary for the induction of many forms of synaptic plasticity. Conventionally, these receptors are thought to act as postsynaptic molecular coincidence detectors, responding to the simultaneous presynaptic release of glutamate and postsynaptic depolarisation. Lately, it has emerged that NMDARs are more diverse; they can also be found at presynaptic locations and may signal metabotropically. However, whilst it is firmly established that postsynaptic NMDARs are important in synaptic plasticity, a possible role for presynaptic NMDARs remains controversial (Bouvier et al., 2018). Pharmacological evidence suggests that blocking presynaptic NMDARs prevents the induction of spike timing-dependent long-term depression (Rodriguez-Moreno & Paulsen, 2008), but possible off-target effects of the drugs used have not been excluded. In this project, you would distinguish between pre- and postsynaptic NMDA receptors using genetic knock-out techniques with subsequent re-introduction of mutated NMDA receptors in specific compartments (pre- and postsynaptic) to more conclusively examine whether they are indeed responsible for the induction of some forms of synaptic plasticity. The techniques used would include patch-clamp recordings in brain slices, optogenetics, and possibly in vivo recordings in anaesthetised animals, building on recent results on sleep related plasticity (Gonzalez-Rueda et al., 2018). The results would help us understand the role of specific signalling pathways involved in synaptic plasticity during development and in the adult brain.

Ole Paulsen

 

Relevant references:

  • Brzosko Z, Schultz W, Paulsen O (2015) Retroactive modulation of spike timing-dependent plasticity by dopamine. eLife 4:e09685.
  • Brzosko ZA, Zannone S, Schultz W, Clopath C, Paulsen O (2017) Sequential neuromodulation of Hebbian plasticity offers mechanism for effective reward-based navigation. eLife 6:e27756.
  • Brzosko Z, Mierau S and Paulsen O (2019) Neuromodulation of spike timing-dependent plasticity: Past, present, and future. Neuron 103: 563-581.

 

Neuromodulation of spike timing-dependent plasticity in the hippocampus

Synaptic plasticity is the leading candidate for a cellular mechanism of learning and memory, but it has been difficult to reconcile the time scales of induction of synaptic plasticity with the time scales of learning. Neuromodulation of synaptic plasticity is a potential mechanism to explain this apparent discrepancy. In particular, different brain states are associated with different activity in cholinergic and dopaminergic inputs (Brzosko et al., 2019). We have recently found that cholinergic and dopaminergic stimulation in the hippocampus can bias plasticity in opposite directions; acetylcholine biases plasticity towards depression, whereas dopamine biases plasticity towards potentiation (Brzosko et al., 2015, 2017). Surprisingly, the effect of dopamine can be retroactive, converting synaptic depression into potentiation when applied after the induction of plasticity (Brzosko et al., 2015). These mechanisms are likely to have important implications for the mechanisms of memory formation. We hypothesise that dopamine, as a reward signal, changes the synaptic weights towards potentiation making the animal more likely to seek rewarded locations, and that cholinergic activity, which is strong during explorative behaviour, enables animals to learn from unrewarded events. A PhD project in this area would combine a basic mechanistic study of neuromodulation of plasticity with elucidating the behavioural consequences of this neuromodulation. Techniques would include electrophysiological recording, optogenetics, and behavioural memory testing. The research should lead to new insights into the mechanisms and functions of synaptic plasticity in the brain.

Dr. Jasper Poort

 

Relevant references:

  • Khan, A.G, Poort, J., Chadwick, A., Blot, A., Sahani, M., Mrsic-Flogel, T., Hofer, S. (2018). Distinct learning-induced changes in stimulus selectivity and interactions of GABAergic interneuron classes in visual cortex. Nature Neuroscience, 21, 851-859. https://doi.org/10.1038/s41593-018-0143-z
  • Poort, J., Khan, A.G., Pachitariu, M., Nemri, A., Orsolic, I., Krupic, J., Bauza, M., Sahani, M., Keller, G., Mrsic-Flogel, T.D., and Hofer, S.B. (2015). Learning Enhances Sensory and Multiple Non-sensory Representations in Primary Visual Cortex. Neuron 86, 1478–1490. https://doi.org/10.1016/j.neuron.2015.05.037

 

Neuronal circuit mechanisms of visual learning and attention

Our brain is constantly bombarded with sensory input but its processing capacity is limited. Selective processing of sensory features relevant for behaviour is therefore crucially important for decision-making. Altered selection of sensory features is linked to cognitive problems in neurodevelopmental disorders including schizophrenia, which affect 3-4% of people. However, the computational brain mechanisms that underlie both normal and abnormal sensory selection are poorly understood.

The aim of this project is to determine how the brain selects relevant visual input, during learning and attention, in the mouse. Mice have a similarly organized visual cortex and show complex decision-making behaviours. Importantly, mouse brain circuits can be measured and manipulated during behaviour in ways not possible in humans. We will test two candidate mechanisms suggested to enhance relevant and suppress irrelevant information: 1) activity of neurons in frontal and parietal decision-making brain areas that activate cells in visual cortex (‘top-down’ input), and 2) activity of inhibitory interneurons in visual cortex.

Our approach is to train head-fixed mice, including pharmacological and genetic mouse models of schizophrenia and healthy controls, in virtual reality environments (VR). In VR, mice actively interact with experimentally controlled visual input and rapidly learn new visually-guided tasks. During learning and attentional task-switching we measure and manipulate large populations of neurons in cortex with 2-photon imaging and optogenetic activation or inactivation of neural activity, using computational modelling to characterize neuronal circuit function (see Poort et al., 2015, and Khan et al., 2018).

Dr. Jasper Poort

 

Relevant references:

  • Meyer, A. O'Keefe, J., Poort, J., (2020). Two distinct types of eye-head coupling in freely moving mice, Current Biology, 11, 2116-2130. https://doi.org/10.1016/j.cub.2020.04.042
  • Meyer, A.F., Poort, J.*, O'Keefe, J., Sahani, M., Linden, J.F. (2018) A head-mounted camera system integrates detailed behavioral monitoring with multichannel electrophysiology in freely moving mice. Neuron, 10, 46-60. https://doi.org/10.1016/j.neuron.2018.09.020

 

Visually-guided decision-making in freely moving mice

Animals actively interact with their environment to gather sensory information. However, animal vision is typically studied in animals passively viewing visual stimuli. Therefore, the behavioural strategies and neural mechanisms that enable animals to optimally sample the visual world during natural behaviours are not yet well understood.

We developed a lightweight head-mounted camera system integrating detailed behavioural monitoring of eye and head movements with multichannel electrophysiology in freely moving mice (Meyer et al., 2018).  With this system we can study for the first time detailed links between behaviour and visual cortical circuits in natural visually-guided behaviours (including exploration and navigation in novel environments to maximize food rewards, and social interactions, see Meyer et al., 2020). We recently discovered that mice make similar ‘saccade and fixate’ eye and head movements as humans (Meyer et al., 2020).

In this project we will investigate how mice use eye and head movements when they learn to optimally sample the environment during different visual tasks, including visual detection and discrimination. We will test the hypothesis that mice learn to optimally target relevant visual features with ‘saccade and fixate’ eye movements during training (collecting behavioural data in humans for comparison). In these mice, we will also measure responses of visual cortical neurons using electrophysiology and optical imaging to characterize how neuronal activity 1) represents visual features 2) is linked to eye and head movement 3) is modified when animals learn to optimally perform different tasks. This will allow us to generate a computational model of how the brain learns to optimally sample visual input during naturalistic decision-making.

Eleanor Raffan

 

Relevant references:

  • https://doi.org/10.1016/j.cmet.2016.04.012
  • https://www.mdpi.com/2073-4425/11/11/1378

 

Understanding the basis of obesity - behavioural and physiological studies in pet dogs.

Canine and human obesity are similar - both are common, associated with health problems and widely attributed to mismanagement of food intake and exercise. However, it is well established that an individual’s genes profoundly alter their tendency to gain weight – true in humans and dogs.  We have identified several genetic variants associated with canine obesity.  These include specific variants which affect the critical leptin-melanocortin pathway and genomic markers from genome-wide association studies. Owner-reported data suggest their effect is mediated in part by altering food-motivation but this remains to be tested systematically.  Additionally, we hypothesise some mutations reduce energy expenditure. Understanding these canine mutations promises to be valuable not only for animal health but also to shed light on the fundamental biology of energy homeostasis in humans.

In this PhD, you will run tests of eating behaviour and energy expenditure in pet dogs, to find out how specific mutations link to obesity in dogs. We have validated a number of playful tests of eating behaviour and use indirect calorimetry (a non-invasive method) to measure energy expenditure. You will recruit owners of dogs of suitable genotype and design and run the experimental work, with plenty of support.

Additionally, you will have the chance to learn some laboratory genetic techniques.  With collaborators you will model the effect of mutations in larger populations.  Throughout, support and training will be provided to ensure you become confident in not only physiological studies but also statistical analysis and epidemiology.

Hugh Robinson, Kevin O'Holleran and Leanne Li (Crick Institute)

 

Relevant references:

  • Monje M, Borniger JC, D’Silva NJ, Deneen B, Dirks PB, Fattahi F, Frenette  PS et al.  (2020) Roadmap for the emerging field of cancer neuroscience. Cell 181: 219–22.
  • Robinson HPC and Li L. (2017). Autocrine, paracrine and necrotic NMDA receptor signalling in mouse pancreatic neuroendocrine tumour cells. Open Biol. 7, 170221.
  • Zeng Q, Michael IP, Zhang P, Saghafinia S, Knott G, Jiao W, McCabe BD, Galván JA, Robinson HPC, Zlobec I, Ciriello G, Hanahan D (2019) Synaptic proximity enables NMDAR signalling to promote brain metastasis. Nature 573:526–531.

Neural signalling and neuroendocrine cancer

The emerging field of cancer neuroscience focuses on how cancer cells interact with the nervous system and utilise neural signalling pathways to drive invasion and metastasis (Monje et al., 2020). Neuroendocrine (NE) tumours arise in many tissues, and include common, highly invasive and lethal cancers such as small-cell lung cancer (SCLC), as well as pancreatic neuroendocrine cancer (PanNET), medullary carcinoma of the thyroid, intestinal carcinoids and neuroblastoma. During progression of breast and prostate cancers into metastatic disease, a small-cell NE phenotype also often evolves. NE tumours are commonly innervated and can metastasise effectively to the brain. However, very little is known of the electrical activity, calcium signalling and secretory function of NE cancer cells, which are key to the normal physiological function of NE cells. Our published and recent unpublished work shows that PanNET and SCLC cells are spontaneously electrically active, causing calcium influx and vesicular secretion (Robinson & Li, 2017; Zeng et al., 2019). We have identified calcium-permeable ion channels involved in this signalling and established that they govern invasiveness of PanNET and also of brain-metastasising breast cancer cells. This project will use 3D culture, advanced lightsheet and super-resolution microscopy, combined with patch-clamp electrophysiology and the use of genetically-encoded calcium sensors and optogenetic probes, to gain a deeper understanding of the roles of electrical, calcium and neurotransmitter signalling in NE cancer invasiveness. As part of this, we will also focus on understanding the signalling between NE cancer cells and neurons.

Fengzhu Xiong

 

Relevant references:

  • Xiong, F., Ma, W., Bénazéraf, B., Mahadevan, L. and Pourquié, O., 2020. Mechanical coupling coordinates the co-elongation of axial and paraxial tissues in avian embryos. Developmental Cell.
  • Vijayraghavan, D.S. and Davidson, L.A., 2017. Mechanics of neurulation: From classical to current perspectives on the physical mechanics that shape, fold, and form the neural tube. Birth defects research, 109(2), pp.153-168.
  • Greene, N.D. and Copp, A.J., 2014. Neural tube defects. Annual review of neuroscience, 37, pp.221-242.

Tissue Mechanics in Neural Tube Morphogenesis

The neural tube is a developmental precursor of the vertebrate central nervous system, including the brain and the spinal cord. It begins as a specified flat epithelial tissue called the neural plate, which then drastically deforms by bilaterally folding towards the midline. As the folds move to meet dorsally, they fuse to close the neural tube with an internal lumen. The folding process happens in conjunction with the morphogenesis of neighboring tissues including the paraxial mesoderm and the surface ectoderm. The failure of this folding and closure process underlies the neural tube defects (NTDs) in human development. From a physics perspective, tissue folding must require driving forces generated by the neural cells and/or the neighboring tissues. In addition, the mechanical properties of the neural tissue may also be regulated to ensure correct tissue deformation progress under the driving forces. The origins and magnitudes of forces from different sources are not well understood, nor are the regulatory mechanisms of tissue rheological properties. Consequently, an integrated picture of biomechanical model of neural tube morphogenesis is missing. To address this challenge, our project will involve (but not limit to) the following approaches using the avian embryonic neural folds as a model system: 1. use imaging to quantify the shape dynamics of the neural plate as it folds towards a tube; 2. use soft gels, magnetic droplets and cantilevers to dissect the contributions from tissue intrinsic (e.g., apical constrictions, intercalations) and extrinsic (e.g., paraxial mesoderm, endoderm) forces to neural tube folding; 3. use molecular and genetic methods to test relevant factors (e.g., cell polarity, adhesion, folate pathway) in regulating tissue biomechanics.

References

Guerreiro, R., Bras, J., 2015. The age factor in Alzheimer’s disease. Genome Med. 7. https://doi.org/10.1186/s13073-015-0232-5

Nilsson, L.-G., Adolfsson, R., Bäckman, L., Frias, C.M. de, Molander, B., Nyberg, L., 2004. Betula: A Prospective Cohort Study on Memory, Health and Aging. Aging Neuropsychol. Cogn. 11, 134–148. https://doi.org/10.1080/13825580490511026

Nilsson, L.-Gör., BÄCkman, L., Erngrund, K., Nyberg, L., Adolfsson, R., Bucht, Gös., Karlsson, S., Widing, M., Winblad, B., 1997. The betula prospective cohort study: Memory, health, and aging. Aging Neuropsychol. Cogn. 4, 1–32. https://doi.org/10.1080/13825589708256633

RSS Feed Latest news

Developmental clock and mechanism of de novo polarization of the mouse embryo

Jan 07, 2021

Study by the Zernicka-Goetz lab highlights the role of zygotic genome activation in regulating the timing of cell polarization

View all news