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Revealing the circuit mechanisms of altered conscious perception with neuropixels recordings and biophysically-inspired neural networks.

Lead Research Organisation: University of Bristol
Department Name: Computer Science

Abstract

Psilocybin is a compound found in 'magic mushrooms' that alters conscious perception. Our goal is to understand how psilocybin changes brain connectivity and conscious perception. To achieve this, we will bring together experts in brain anatomy and function with experts in artificial intelligence. We will first analyse and combine data on the brain's anatomy and function. We will use this data to simulate the effects of psilocybin on the brain's circuits. We can then analyse the simulation to learn how psilocybin changes brain activity and the conscious experience.

Psilocybin has exploded in popularity as a recreational drug, a mental health treatment and an aid for creativity. The popularity derives in part from its effects on conscious perception. Conscious perception emerges from activity across scales of brain organisation. We aim to integrate across these scales. In this way, we will learn how the local effects of psilocybin lead to reorganisation of connections across the brain.

The nature of the psilocybin experience does not only depend on biological factors. The mental state of the person taking the drug also affects the experience. We need to know how mental states can change psilocybin's effects on neural circuits. This would show how psychological and biological factors influence each other and determine our experience. Both natural chemical transmitters and drugs bind with receptors to open channels in neurons, much as a key fits a lock to open a door. We recently found the receptors that psilocybin binds to in different amounts across different brain areas. We aim to test whether this can explain the powerful influence of psilocybin on conscious perception.

We propose to use a new advanced recording technology to measure psilocybin's effects on the activity of hundreds of neurons in the rat brain. We will combine this data with our maps
of the locations of receptors in the brain. We will use this data to build a simulation of psilocybin's effects on the brain based on real biology. This will provide a missing link between the psychological and biological effects of psilocybin. Scientists can use this to design and refine future experiments.

We have three key objectives:

1. To analyse recordings of neural activity from the rat brain to identify how psilocybin's changes brain architecture.
2. To simulate how the mental state can combine with biological factors and alter the psilocybin experience
3. To simulate how the brain's physiology and anatomy determine psilocybin's ability to alter conscious perception.

This project will create an open software platform to advance our understanding of psychedelic drugs. This has the potential to move forward both our fundamental understanding of the brain and drug development.

Technical Summary

Psilocybin is a psychedelic drug that alters conscious perception. The goal of this project is to pinpoint the critical changes to neural circuit physiology that produce these alterations. We will achieve this by integrating anatomy, physiology and imaging data with neural network models of cognition.

Psilocybin has exploded in popularity as a recreational drug and a mental health treatment. However, relatively little is known about how psilocybin affects neural circuitry locally or across the cortex. The psilocybin experience is also affected by contextual factors such as cognitive state. We need to know how cognitive states modulate psilocybin's effects on neural circuit interactions. This would show how the psychological and pharmacological determinants of subjective experience interact. At the pharmacological level, psilocybin acts on the 5-HT1A and 5-HT2 receptors. We recently discovered that 5-HT1A and 5-HT2 receptors have contrasting expression across the cortex. We aim to test whether this can account for psilocybin's powerful influence on tasks of conscious perception.

We have three key objectives:
1. To analyse large-scale chronic neural recordings to identify how psilocybin's circuit-level effects change the functional network organisation across the rat frontal cortex.
2. To construct a biophysically-inspired neural network model to determine the circuit and network level mechanisms behind psilocybin's state-dependent effects on neural activity.
3. To develop a biophysically-inspired neural network model of the human cortex, to test whether the effects of psilocybin on neural circuit physiology, and the serotonin receptor expression in the human brain can account for psilocybin's ability to alter conscious perception.

This project will create an open software platform and a framework for analysis and interpretation of the effects of psychoactive drugs, informing both discovery neuroscience and drug development.
 
Description 1. Mapping Serotonin and Other Receptors Across Species
We generated new insights into how neural circuits are organised by comparing neurotransmitter receptor distributions in rodent, macaque, and human brains. By analysing data on the receptor and gene expression across most of the cortex, we identified two major axes of cortical organisation. This principal axis spans from sensory to higher cognitive areas and is defined by neurons hosting an increased quantity of all types of neurotransmitter receptors. The second major axis is defined principally by the expression of serotonin receptors, which we found to vary between networks in the brain that are responsible for our attention being directed either to the external sensory environment (Dorsal Attention Network), or to internal thoughts (Default Mode Network). We also identified similar expression of serotonin receptors and their genes in humans, macaque monkeys and, to some extent, rats. This clarifies the translational potential of macaques and rats for understanding psilocybin's circuit-level effects on neural activity.
2. Circuit-Resolution Dynamics of Psilocybin in the Rat Frontal Cortex
By recording large-scale, chronic neural activity in freely behaving rats, we found that single doses of psilocybin induce decreased pyramidal cell firing, slowed neural dynamics and reduced the complexity of neural signalling. Intriguingly, after this acute phase, synchrony in certain frequency bands of the local field potiential (thought to indirectly measure synaptic activity) rose over subsequent days. These observations suggest that psilocybin's short-term network inhibition is followed by longer-term changes in frontal cortical dynamics, offering insights into psilocybin's putative plasticity-promoting effects that could be relevant for novel mental health interventions.
3. Biophysically-Inspired Modelling of Multiregional Cortical Function
We developed and tested large-scale computational models of rodent, macaque, and human cortices to explain large-scale neural activity during conscious perception and and cognition. Crucially, we incorporated anatomical data on connectivity, and the types of neurons and receptors expressed across cortical areas to explain how the observed neural dynamics arise. The models successfully reproduced anti-correlated activity between the default mode and dorsal attention networks, which has been observed experimentally. Combined with our anatomical findings, this gives us initial insight into how psilocybin may alter the balance between internally- and externally-focused perception and cognition.
4. Prototype Models Bridging Neuroscience and Machine Learning
Finally, we developed prototype machine learning-inspired models to link psilocybin's acute perceptual effects with its longer-term influence on plasticity and circuit reconfiguration. While still preliminary, these approaches highlight a promising avenue for unifying our empirical data-from single-neuron firing patterns to large-scale network dynamic -with computational frameworks that can systematically test how serotonergic modulation might affect our conscious perception and ultimately our mental health.

Overall, our work reveals psilocybin's circuit-level impact, underscores the importance of cross-species receptor mapping, and advances computational methods that bridge across scales of neuroscience, from single neurons to brain-wide activity and conscious perception.
Exploitation Route Our receptor distribution data, neural recordings, and computational models offer a foundation that neuroscientists can use to interpret their own data, and refine theories of cortical function and consciousness. Clinical researchers and pharmaceutical companies can use the results on receptor distributions and acute and chronic circuit effects of psilocybin to inform evidence-based drug discovery.
Sectors Pharmaceuticals and Medical Biotechnology

URL https://www.biorxiv.org/content/10.1101/2024.12.10.627734v1
 
Title A multi-scale model of a cognitive function in the rodent brain 
Description We developed a large-scale model of the multiregional rodent brain for a cardinal cognitive function called working memory, the brain's ability to internally hold and process information without sensory input. The model is built on mesoscopic connectome data for interareal cortical connections and endowed with a macroscopic gradient of measured parvalbumin-expressing interneuron density. This model provides a framework to interpret large-scale recordings of brain activity during cognition. 
Type Of Material Computer model/algorithm 
Year Produced 2024 
Provided To Others? Yes  
Impact This model has been influential for new anatomical discoveries by other groups working in the rodent brain. In particular, it was a key reference for the following paper: Courcelles, Erik Justin, Kasper Kjelsberg, Laura Convertino, Rajeevkumar Raveendran Nair, Menno P. Witter, and Maximiliano José Nigro. "Association cortical areas in the mouse contain a large population of fast-spiking GABAergic neurons that do not express parvalbumin." European Journal of Neuroscience 59, no. 12 (2024): 3236-3255. 
URL https://github.com/XY-DIng/mouse_dist_wm
 
Title Neurotransmitter receptor densities per neuron across macaque cortex 
Description Neurotransmitter receptors constitute key molecules in signal transduction, and the degree to which they modulate neural activity is dependent on the number of receptors expressed on the neuronal membrane. Receptors for classical neurotransmitters are heterogeneously distributed throughout the macaque monkey cerebral cortex, as are neuronal densities. We applied in vitro receptor autoradiography to quantify the densities of 14 different receptor types in 109 cytoarchitectonically identified areas located throughout the macaque cortex. We used previously published neuron density data (Collins et al., Proc Natl Acad Sci 107: 15927-15932, 2010) to estimate the receptor density per neuron in each area. This data can be used to build biologically informed neuronal computational models. 
Type Of Material Database/Collection of data 
Year Produced 2023 
Provided To Others? Yes  
Impact This data has been used as a basis for computational models of the brain e.g. Zou, Licheng, Nicola Palomero-Gallagher, Douglas Zhou, Songting Li, and Jorge F. Mejias. "Distributed evidence accumulation across macaque large-scale neocortical networks during perceptual decision making." bioRxiv (2023): 2023-12. This data has further been used to analyse and interpret other datasets by leading groups in the field: Autio, Joonas A., Ikko Kimura, Takayuki Ose, Yuki Matsumoto, Masahiro Ohno, Yuta Urushibata, Takuro Ikeda, Matthew F. Glasser, David C. Van Essen, and Takuya Hayashi. "Mapping vascular network architecture in primate brain using ferumoxytol-weighted laminar MRI." bioRxiv (2024). 
URL https://search.kg.ebrains.eu/instances/de62abc1-7252-4774-9965-5040f5e8fb6b
 
Description Cross-species gene and receptor expression 
Organisation McGill University
Department Montreal Neurological Institute and Hospital
Country Canada 
Sector Hospitals 
PI Contribution We have now collaborated with Prof. Bratislav Misic's team (Montreal Neurological Institute, Canada) to build on our work (Froudist-Walsh et al., Nature Neuroscience, 2023) to compare macaque gene and receptor expression with each other and with human gene expression (Lupp et al., Science Advances, 2025). My team provided macaque receptor data, and analyses and interpretation of data. We also collaborated on writing the manuscript.
Collaborator Contribution Our partners initiated the project, and performed the analyses of gene expression data in humans and macaques, as well as their comparison
Impact 10.1126/sciadv.ads6967 This is a multidisciplinary collaboration: neuroscience, data science, genomics, anatomy
Start Year 2024
 
Description Psilocybin cross-level cross-species 
Organisation Julich Research Centre
Country Germany 
Sector Academic/University 
PI Contribution Our computational neuroscience team at the University of Bristol initiated the collaboration, devised the scientific framework for the collaboration, developed computational tools for data analysis and modelling, arranged meetings of the collaborative team, provided direct training for one postdoctoral researcher and indirect training through meetings for another postdoctoral researcher.
Collaborator Contribution Prof. Carhart-Harris has provided expertise on psilocybin's effects on the human brain. He has also provided access to - and expert knowledge of - resting-state fMRI data of human subjects undergoing psilocybin administration. Lastly, he has agreed to host the Postdoctoral Research Associate in UCSF for one week. Prof. Palomero-Gallagher has provided expertise the receptor anatomy and principals of organization of the rat and human brain. She has also provided access to unique in-vitro 5-HT1A and 5-HT2 receptor autoradiography data that her lab has collected from across dozens of regions of the rat and human cortex. Prof. Matt Jones has provided expertise with neurophysiology data and translational neuroscience. Furthermore, his lab and in particular postdoctoral research associate Dr. Ross Purple conducted the experiments. We have regularly met in order to provide cross-disciplinary training for Postdoctoral Research Associate Dr. Rahul Gupta in neurophysiology and neuroanatomy. Dr. Gupta was previously trained in theoretical and computational neuroscience. This project has enabled Dr. Gupta to undertake a much more direct collaboration with experimental neuroscientists and their data than previously, and to build up his skills toolkit, with major advances in large-scale neurophysiological data analysis and training recurrent neural network models to fit such data. This has also led to advances for the entire team in cross-disciplinary understanding.
Impact This collaboration is highly multidisciplinary. The primary disciplines involved are neuroanatomy, neurophysiology, neuroimaging, translational neuroscience, computational neuroscience and artificial intelligence. Publication: (Note that collaboration between SFW & NPG was initiated before 2023, but its continuation was enabled by this grant. All other aspects of this collaboration are new, arising from this grant). DOI: 10.1038/s41593-023-01351-2 Conference presentation: CoSyNe Workshop talk (2024). Lisbon. BBSRC Workshop talk (2023). Oxford. Outreach talks: Brain Awareness Week (2024). Bristol Neuroscience Festival (2023). "The neuroscience of normal and abnormal conscious experiences".
Start Year 2023
 
Description Psilocybin cross-level cross-species 
Organisation University of Bristol
Country United Kingdom 
Sector Academic/University 
PI Contribution Our computational neuroscience team at the University of Bristol initiated the collaboration, devised the scientific framework for the collaboration, developed computational tools for data analysis and modelling, arranged meetings of the collaborative team, provided direct training for one postdoctoral researcher and indirect training through meetings for another postdoctoral researcher.
Collaborator Contribution Prof. Carhart-Harris has provided expertise on psilocybin's effects on the human brain. He has also provided access to - and expert knowledge of - resting-state fMRI data of human subjects undergoing psilocybin administration. Lastly, he has agreed to host the Postdoctoral Research Associate in UCSF for one week. Prof. Palomero-Gallagher has provided expertise the receptor anatomy and principals of organization of the rat and human brain. She has also provided access to unique in-vitro 5-HT1A and 5-HT2 receptor autoradiography data that her lab has collected from across dozens of regions of the rat and human cortex. Prof. Matt Jones has provided expertise with neurophysiology data and translational neuroscience. Furthermore, his lab and in particular postdoctoral research associate Dr. Ross Purple conducted the experiments. We have regularly met in order to provide cross-disciplinary training for Postdoctoral Research Associate Dr. Rahul Gupta in neurophysiology and neuroanatomy. Dr. Gupta was previously trained in theoretical and computational neuroscience. This project has enabled Dr. Gupta to undertake a much more direct collaboration with experimental neuroscientists and their data than previously, and to build up his skills toolkit, with major advances in large-scale neurophysiological data analysis and training recurrent neural network models to fit such data. This has also led to advances for the entire team in cross-disciplinary understanding.
Impact This collaboration is highly multidisciplinary. The primary disciplines involved are neuroanatomy, neurophysiology, neuroimaging, translational neuroscience, computational neuroscience and artificial intelligence. Publication: (Note that collaboration between SFW & NPG was initiated before 2023, but its continuation was enabled by this grant. All other aspects of this collaboration are new, arising from this grant). DOI: 10.1038/s41593-023-01351-2 Conference presentation: CoSyNe Workshop talk (2024). Lisbon. BBSRC Workshop talk (2023). Oxford. Outreach talks: Brain Awareness Week (2024). Bristol Neuroscience Festival (2023). "The neuroscience of normal and abnormal conscious experiences".
Start Year 2023
 
Description Psilocybin cross-level cross-species 
Organisation University of California, San Francisco
Country United States 
Sector Academic/University 
PI Contribution Our computational neuroscience team at the University of Bristol initiated the collaboration, devised the scientific framework for the collaboration, developed computational tools for data analysis and modelling, arranged meetings of the collaborative team, provided direct training for one postdoctoral researcher and indirect training through meetings for another postdoctoral researcher.
Collaborator Contribution Prof. Carhart-Harris has provided expertise on psilocybin's effects on the human brain. He has also provided access to - and expert knowledge of - resting-state fMRI data of human subjects undergoing psilocybin administration. Lastly, he has agreed to host the Postdoctoral Research Associate in UCSF for one week. Prof. Palomero-Gallagher has provided expertise the receptor anatomy and principals of organization of the rat and human brain. She has also provided access to unique in-vitro 5-HT1A and 5-HT2 receptor autoradiography data that her lab has collected from across dozens of regions of the rat and human cortex. Prof. Matt Jones has provided expertise with neurophysiology data and translational neuroscience. Furthermore, his lab and in particular postdoctoral research associate Dr. Ross Purple conducted the experiments. We have regularly met in order to provide cross-disciplinary training for Postdoctoral Research Associate Dr. Rahul Gupta in neurophysiology and neuroanatomy. Dr. Gupta was previously trained in theoretical and computational neuroscience. This project has enabled Dr. Gupta to undertake a much more direct collaboration with experimental neuroscientists and their data than previously, and to build up his skills toolkit, with major advances in large-scale neurophysiological data analysis and training recurrent neural network models to fit such data. This has also led to advances for the entire team in cross-disciplinary understanding.
Impact This collaboration is highly multidisciplinary. The primary disciplines involved are neuroanatomy, neurophysiology, neuroimaging, translational neuroscience, computational neuroscience and artificial intelligence. Publication: (Note that collaboration between SFW & NPG was initiated before 2023, but its continuation was enabled by this grant. All other aspects of this collaboration are new, arising from this grant). DOI: 10.1038/s41593-023-01351-2 Conference presentation: CoSyNe Workshop talk (2024). Lisbon. BBSRC Workshop talk (2023). Oxford. Outreach talks: Brain Awareness Week (2024). Bristol Neuroscience Festival (2023). "The neuroscience of normal and abnormal conscious experiences".
Start Year 2023
 
Description Access to Bristol 
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 I twice spoke in 2023, 2024 about computer science, engineering and neuroscience, using examples from our BBSRC funded research, to students from Widening Participation backgrounds on the Access to Bristol programme. In both 2023 and 2024, 100% of responding students agreed that "the session was interesting", "I developed my knowledge of the subject", "the lecturer's explanations were clear and understandable" and "I feel more prepared in applying to study my chosen subject at the University of Bristol". Here is some example feedback: "It was very interesting and engaging", "The independent/group thinking tasks helped to foster a sense of understanding as it promoted thought", "it was delivered in a good understandable way", "I loved the session, it was my favourite one. I feel more interested about the subject."
Year(s) Of Engagement Activity 2023,2024
URL https://www.bristol.ac.uk/study/outreach/post-16/access/
 
Description Bristol Neuroscience Festival 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact The Bristol Neuroscience Festival attracted more than 4,000 visitors, some of whom travel great distances to attend.

It took place over three days, with the first day open to primary schools, the second day for secondary schools and the final day open to the general public. The event brings together researchers and students from across the Bristol Neuroscience remit (Life Science, Health Science, NHS, Engineering etc) as well the Royal West of England Academy who support our Schools and Community Brain Art competition and local charity groups (Glenside Hospital Museum, Bristol Drugs Project, Medical Research Council (MRC) Brain Bank and mental health charity Off the Record).

The Festival offers visitors of all ages the chance to talk to our world class scientists and clinicians, undertake hands-on activities, receive careers and admissions advice, take part in experiments and attend our Best of Bristol research talks. The 3-day event closes with a public lecture in the Victoria Rooms. For this lecture we invited Prof. David Nutt (Imperial College London) and Prof. Emma Robinson (University of Bristol) to speak about "How psychedelic medicine is changing our understanding of psychiatric
disorders, their treatments, and the fundamental biology of the brain". This event was fully booked several weeks before the Festival started and extremely well received by those in attendance.

Our research team created an interactive stand to promote active learning and interaction from the students and public with our research. This was a resounding success, with several children, and even a couple of adults asking what they needed to study to do neuroscience research.

Our team further gave two sold-out public talks on our research, with very positive feedback (120 people for each talk, Sean Froudist Walsh and Matt Jones) . This included students interested in following up about how to enter neuroscience research.

Evaluation Methods
Post-event questionnaires were completed by 15 school teachers with regard to the 746 pupils they supervised on the day.
A further 182 responses were completed by pupils attending the secondary school day and 113 people attending the general public day on 4th March. Thus our responses relate to 1041 individuals. This reflected approximately 25% of the total number of people attending the festival.

There was 94% satisfaction rating from schools, with 94% saying they found the festival interesting and informative and 92% saying they would share their experience with friends or family. Of the general public, 99% would recommend the festival, 98% found it interesting and informative and 92% will share what they learned.
Year(s) Of Engagement Activity 2023
URL https://www.bristol.ac.uk/neuroscience/bnf/2023-event/
 
Description Press release following receptor article - reported by 41 international news agencies 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact We arranged press releases from the University of Bristol and the Research Centre Julich to accompany our publication in Nature Neuroscience on cortical receptor organisation and cross-species comparison in serotonin receptor organisation.

This was picked up by 41 international news outlets, including La Vanguardia (Spain), Times of India, Il Fatto Quotidiano (Italy).

Altmetric has classified the article as in the 99th percentile of all publications of a similar age for attention, with posts on Twitter/X directly linking to the article being seen by up to 1,153,271 followers (upper bound).
Year(s) Of Engagement Activity 2023
URL https://www.altmetric.com/details/150276005
 
Description Work experience talk for students from Widening Participation backgrounds 
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 I spoke about engineering and neuroscience, using examples from our BBSRC funded research, to students from Widening Participation backgrounds on the Engineering Work Experience programme.

Here is some example feedback:
'I was surprised at the advancements with neuroscience and the freedom students were given in designing and using the university's resources'
'The lecture at the end because it was really interesting, and I learned about neuro engineering which I didn't know anything about'
'The talk about neuroscience was my favourite - I really like AI so it was super interesting to see the applications'
'I enjoyed the neuroscience lecture because I enjoyed learning about the implications that neuroscience could have on medicine and engineering in the near future'
'The variety of engineering careers such as the links with neuroscience'
'The computational neuroscience talk was the most surprising I didn't really know about that stuff before that talk!'
Year(s) Of Engagement Activity 2023