Defining the genetic and activity-dependent instructions for striatal circuit development
Lead Research Organisation:
University of Oxford
Department Name: Pharmacology
Abstract
Newly born nerve cells, or neurons in the brain, contain a set of instructions written in their genes, which together with messages they receive from neighbouring neurons, guides their development. These factors will determine the type of neuron it will become and determine which other neurons it will make contacts with and form a neural circuit. Errors in the development of neural circuits at these early stages can lead to problems later in life. For instance, schizophrenia, Tourette's syndrome and autism are disorders where abnormal developmental events have been proposed to underlie aberrant communication in the adult brain. This programme of research will investigate the contribution of both intrinsic genetic instructions and extrinsic activity patterns to the development of the correct wiring of neurons in the striatum, a part of the brain essential for the planning and execution of movements. It has been observed that the striatum consists of two segregated pathways of information flow and that these pathways need to communicate with each other at a precise level for normal function. The experiments outlined in this proposal will investigate how much crosstalk exists between these two pathways and how genetic instructions and early life extrinsic inputs instruct the degree of crosstalk. Findings from this work will advance our understanding of foetal and neonatal brain development, with follow-on implications for our understanding of cellular changes that occur in common disorders of the nervous system.
Technical Summary
The aim of the proposed study is to dissect out the role of genetic and activity-dependent factors in coordinating the development of recurrent inhibitory connectivity between striatal medium spiny projection neurons (MSNs), which is shown to be disrupted in a variety of basal ganglia disorders. I will employ in vitro and in vivo electrophysiology in mice to define the development of synaptic connectivity between MSNs under baseline conditions and after disruption of early activity patterns. Furthermore, I will genetically label different types of MSN with fluorescent probes to investigate the role of genes in coordinating striatal recurrent connectivity. These complementary experiments will define critical factors and processes in the development of the striatum and can guide new rationales and identify targets for intervention in a range of basal ganglia disorders.
Planned Impact
This work will directly advance our knowledge of the development of neural circuits and circuit connectivity and lead to conceptual advancements in our understanding of the brain. A detailed mechanistic understanding of neural circuit formation and connectivity will guide new rationales and identify targets for intervention in a range of neurological disorders and will be relevant for clinicians, the pharmaceutical industry and smaller biotech companies contributing to the development of new treatments. For example, an understanding of the fine scale connectivity of the striatum can guide improved targeting and stimulation paradigms for deep brain stimulation. Furthermore, knowing the roles for intrinsic genetic factors and extrinsic activity-dependent instructions in the development of connectivity between neurons will provide insight into novel strategies for improved integration of neural precursors in stem cell-based treatments. The pharmaceutical industry has en masse reduced or terminated their neuroscience R&D for which a lack of understanding of many basic aspects of brain function is to blame. Therefore, an increased understanding of basic mechanistic processes is tantamount for the return of this vital industry to spur discovery of new treatments and drugs for neurological disorders. Secondly, the ability of clinicians and the pharmaceutical industry to transform basic biomedical advancements into direct treatments for patients in clinics will improve the health and wellbeing of humans although this process is slow and can take many years, as discoveries in non-humans have to be validated in both healthy participants and patients. I intend to impact patients and patients groups more directly through meetings in which I can share new findings and concepts. Thirdly, it is important for policy makers to be aware of the possibilities and limitations of basic biomedical research. This necessitates a dialogue with policy makers and puts responsibility with scientists to both engage with policy makers and promote research. This will impact the thinking and decision-making on scientific subjects and will improve evidence-based policy and understanding of the processes underlying scientific discovery. An correct understanding of the opportunities and limitations is crucial as policy makers have the power to fund large projects as recently showcased by the US government (The Brain Iniative; http://www.nih.gov/science/brain/) and European governments (Human Brain Project; https://www.humanbrainproject.eu/en_GB) and need to base their decision making on as good an understanding as possible. Fourthly, it is important that general public is aware of what scientists do and how they do it as science constantly pushes boundaries and their needs to be a dialogue with the public what is and isn't acceptable (e.g. cloning issues). Lastly, the research will directly impact the health and wealth of the United Kingdom by increasing its prestige and will attract international scientists and other skilled people to the workforce.
Publications
Bocchio M
(2016)
Sleep and Serotonin Modulate Paracapsular Nitric Oxide Synthase Expressing Neurons of the Amygdala.
in eNeuro
Bolam JP
(2016)
Histamine and the striatum.
in Neuropharmacology
Carthy E
(2021)
Histamine, Neuroinflammation and Neurodevelopment: A Review.
in Frontiers in neuroscience
Ellender TJ
(2019)
Embryonic progenitor pools generate diversity in fine-scale excitatory cortical subnetworks.
in Nature communications
Han S
(2020)
Histaminergic Control of Corticostriatal Synaptic Plasticity during Early Postnatal Development.
in The Journal of neuroscience : the official journal of the Society for Neuroscience
Klavinskis-Whiting S
(2023)
Generation and propagation of bursts of activity in the developing basal ganglia
in Cerebral Cortex
Knowles R
(2021)
From Progenitors to Progeny: Shaping Striatal Circuit Development and Function.
in The Journal of neuroscience : the official journal of the Society for Neuroscience
Description | John Fell OUP Fund |
Amount | £40,000 (GBP) |
Funding ID | 162/059 |
Organisation | University of Oxford |
Sector | Academic/University |
Country | United Kingdom |
Start | 05/2017 |
End | 04/2019 |
Description | Newton International Fellowships 2018 - Mr Ricardo Marquez Gomez |
Amount | £66,000 (GBP) |
Funding ID | NIF\R1\180147 |
Organisation | The Royal Society |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 03/2019 |
End | 03/2021 |
Title | Public deposit of custom code for analysis of RNA sequencing data |
Description | Custom code has been made available on the website github for analysis of RNA sequencing data |
Type Of Material | Technology assay or reagent |
Year Produced | 2019 |
Provided To Others? | Yes |
Impact | The code has been downloaded multiple times. |
URL | https://github.com/jscaber/cgat-proj057 |
Title | Deposit of reconstructed neuronal morphologies on public database Ellender et al. |
Description | Neurolucida reconstructions of cortical L4 and L2/3 neurons which are part of Ellender et al, 2019, Nature Communications and can be by computational neuroscientist to generate more realistic neuronal models. |
Type Of Material | Database/Collection of data |
Year Produced | 2020 |
Provided To Others? | Yes |
Impact | Only recently uploaded so has no demonstrable impact as of yet. |
URL | http://neuromorpho.org |
Title | Public deposit reconstructed neurons Krajeski et al. |
Description | Neurolucida reconstructions of striatal spiny projection neurons in 4 different age ranges which are part of Krajeski et al, 2019, Journal of Physiology and can be by computational neuroscientist to generate more realistic neuronal models. |
Type Of Material | Database/Collection of data |
Year Produced | 2020 |
Provided To Others? | Yes |
Impact | Uploaded recently so too early to have impact. |
URL | http://neuromorpho.org |
Title | Public deposit reconstructed neurons from manuscript van Heusden et al. |
Description | Public deposit reconstructed neurons from manuscript van Heusden et al. 2019 which can be by computational neuroscientist to generate more realistic neuronal models. |
Type Of Material | Database/Collection of data |
Year Produced | 2020 |
Provided To Others? | Yes |
Impact | Too early to say. |
URL | http://neuromorpho.org |
Description | In vivo neonatal recordings of brain activity |
Organisation | University Medical Center Hamburg-Eppendorf |
Department | Center For Molecular Neurobiology Hamburg |
Country | Germany |
Sector | Academic/University |
PI Contribution | Proposal has been made for a group of experiments. We have contributed time and visits to the lab of Hamburg to discuss the timeline of experiments. |
Collaborator Contribution | Partner has provided intellectual and practical support for a set of experiments and the setup of these recording techniques at Oxford University. |
Impact | Exchange of protocols and practical help with the setup of an in vivo recording rig at Oxford University to perform recordings of neonatal brain activity. |
Start Year | 2015 |
Description | Attendance at ARUK public event |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | 50+ people attended an annual public event organised by the University of Oxford, as part of the Alzheimer's Research UK Thames Valley network centre at the John Radcliffe hospital. The day included talks on Alzheimer's, dementia, current treatments and the latest research which sparked questions and discussion afterwards. Also impacted on my own views and understanding of Alzheimer's disease and my current research priorities. |
Year(s) Of Engagement Activity | 2020 |
URL | https://www.oxdare.ox.ac.uk/aruk |
Description | DPhil Careers Advice Panel |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Postgraduate students |
Results and Impact | Took part in a panel discussion with both senior and junior PIs in front of current PhD students to discuss career progression and options both within and outside of academia. |
Year(s) Of Engagement Activity | 2019 |
Description | Generating Genius programme |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Schools |
Results and Impact | 40 pupils attended for a school visit to the research organisation as part of the MRC Festival of Medical Research, which sparked questions and discussion afterwards, and the school reported increased interest in related subject areas. |
Year(s) Of Engagement Activity | 2016 |
URL | https://www.mrcbndu.ox.ac.uk/news/generating-genius-pupils-visit-unit-learn-more-about-brain-researc... |
Description | In2Science work experience students |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Schools |
Results and Impact | in2scienceUK is an award winning organisation which gives students from low income backgrounds the opportunity to work alongside STEM scientists, and receive the advice and information they need to progress to University and STEM careers. Intelligent pupils from underprivileged backgrounds and traditionally low achieving schools face major obstacles resulting in few pupils obtaining a place at top universities. This scheme aims to change this by offering those who are bright the chance to work alongside scientists. This enables students to develop their scientific, written and oral communication skills, therefore supporting them in their university applications. |
Year(s) Of Engagement Activity | 2016 |
URL | https://www.mrcbndu.ox.ac.uk/news/unit-and-in2scienceuk-deliver-more-stem-placements-school-pupils |
Description | Invited seminar at the INMED / INSERM (France) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | 50+ people attended my invited seminar which sparked questions and discussions. It led to new contacts for future collaborative projects. |
Year(s) Of Engagement Activity | 2020 |
Description | MRC Schools Open Day 2017 |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Schools |
Results and Impact | More than 120 pupils and teachers as well as 2 Oxford city councillors attended for a school visit to our research organisation, which sparked questions and discussion afterwards. |
Year(s) Of Engagement Activity | 2017 |
URL | https://www.mrcbndu.ox.ac.uk/news/schools-open-day-2017 |
Description | Medical Sciences Doctoral Training Centre Annual Symposium - Career Advice |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Postgraduate students |
Results and Impact | Give a 10-15 minute talk on my career and then join a panel for a Question and Answer session on current work, how I decided to follow the career that I went into, how my DPhil has helped me and any top tips (or pitfalls to avoid) for those currently thinking through their next steps. The Q&A session involved other alumni of the MSDTC and some academics answering questions posed by the students. |
Year(s) Of Engagement Activity | 2018 |
URL | https://www.medsci.ox.ac.uk/study/graduateschool/courses/dtc-structured-research-degrees |
Description | Schools visit + local politicians to Department of Pharmacology 2020 |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Schools |
Results and Impact | More than 100 pupils and teachers and local politicians attended a schools visit to the Department of Pharmacology. Demonstration of research technology and latest findings which sparked questions and discussions afterwards. |
Year(s) Of Engagement Activity | 2020 |
Description | Seminar at the Department of Neuroscience, Psychology & Behaviour at Leicester University |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Postgraduate students |
Results and Impact | 50+ people attended my invited seminar which sparked questions and discussions. It led to new contacts for future collaborative projects. |
Year(s) Of Engagement Activity | 2019 |
Description | Setup of Twitter account for the lab |
Form Of Engagement Activity | Engagement focused website, blog or social media channel |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Other audiences |
Results and Impact | A Twitter account was setup for my laboratory to increase the exposure and impact of my outputs from my lab. In 4 years time I have managed to accrue >350 followers. |
Year(s) Of Engagement Activity | 2015 |
URL | https://twitter.com/tommasellender?lang=en |