Immune and metabolic regulation of sensorimotor physiology and repair

Cognitive maps as expectations learned across episodes – a model of the two dentate gyrus blades

How can the hippocampal system transition from episodic one-shot learning to a multi-shot learning regime and what is the utility of the resultant neural representations? This talk will explore the role of the dentate gyrus (DG) anatomy in this context. The canonical DG model suggests it performs pattern separation. More recent experimental results challenge this standard model, suggesting DG function is more complex and also supports the precise binding of objects and events to space and the integration of information across episodes. Very recent studies attribute pattern separation and pattern integration to anatomically distinct parts of the DG (the suprapyramidal blade vs the infrapyramidal blade). We propose a computational model that investigates this distinction. In the model the two processing streams (potentially localized in separate blades) contribute to the storage of distinct episodic memories, and the integration of information across episodes, respectively. The latter forms generalized expectations across episodes, eventually forming a cognitive map. We train the model with two data sets, MNIST and plausible entorhinal cortex inputs. The comparison between the two streams allows for the calculation of a prediction error, which can drive the storage of poorly predicted memories and the forgetting of well-predicted memories. We suggest that differential processing across the DG aids in the iterative construction of spatial cognitive maps to serve the generation of location-dependent expectations, while at the same time preserving episodic memory traces of idiosyncratic events.

SWEBAGS conference 2024: The basal ganglia in action

Fragile minds in a scary world: trauma and post traumatic stress in very young children

Post traumatic stress disorder (PTSD) is a prevalent and disabling condition that affects larger numbers of children and adolescents worldwide. Until recently, we have understood little about the nature of PTSD reactions in our youngest children (aged under 8 years old). This talk describes our work over the last 15 years working with this very young age group. It overviews how we need a markedly different PTSD diagnosis for very young children, data on the prevalence of this new diagnostic algorithm, and the development of a psychological intervention and its evaluation in a clinical trial.

Developmental disorders of presynaptic vesicle cycling - Synaptotagmin-1 and beyond

Post-diagnostic research on rare genetic developmental disorders presents new opportunities (and a few challenges) for discovery neuroscience and translation. In this talk, Kate will describe and discuss neurodevelopmental phenotypes arising from rare, high penetrance genomic variants which directly influence pre-synaptic vesicle cycling (SVC disorders). She will focus on Synaptotagmin-1 Associated Neurodevelopmental Disorder (also known as Baker Gordon Syndrome), first described in 2015 and now diagnosed in more than 50 children and young people worldwide. She will then present work-in-progress by her group on the neurodevelopmental spectrum of SVC disorders more broadly, and discuss opportunities for collaborative neuroscience which can bridge the gaps between genetic cause and complex neurological, cognitive and mental health outcomes.

The Synaptome Architecture of the Brain: Lifespan, disease, evolution and behavior

The overall aim of my research is to understand how the organisation of the synapse, with particular reference to the postsynaptic proteome (PSP) of excitatory synapses in the brain, informs the fundamental mechanisms of learning, memory and behaviour and how these mechanisms go awry in neurological dysfunction. The PSP indeed bears a remarkable burden of disease, with components being disrupted in disorders (synaptopathies) including schizophrenia, depression, autism and intellectual disability. Our work has been fundamental in revealing and then characterising the unprecedented complexity (>1000 highly conserved proteins) of the PSP in terms of the subsynaptic architecture of postsynaptic proteins such as PSD95 and how these proteins assemble into complexes and supercomplexes in different neurons and regions of the brain. Characterising the PSPs in multiple species, including human and mouse, has revealed differences in key sets of functionally important proteins, correlates with brain imaging and connectome data, and a differential distribution of disease-relevant proteins and pathways. Such studies have also provided important insight into synapse evolution, establishing that vertebrate behavioural complexity is a product of the evolutionary expansion in synapse proteomes that occurred ~500 million years ago. My lab has identified many mutations causing cognitive impairments in mice before they were found to cause human disorders. Our proteomic studies revealed that >130 brain diseases are caused by mutations affecting postsynaptic proteins. We uncovered mechanisms that explain the polygenic basis and age of onset of schizophrenia, with postsynaptic proteins, including PSD95 supercomplexes, carrying much of the polygenic burden. We discovered the “Genetic Lifespan Calendar”, a genomic programme controlling when genes are regulated. We showed that this could explain how schizophrenia susceptibility genes are timed to exert their effects in young adults. The Genes to Cognition programme is the largest genetic study so far undertaken into the synaptic molecular mechanisms underlying behaviour and physiology. We made important conceptual advances that inform how the repertoire of both innate and learned behaviours is built from unique combinations of postsynaptic proteins that either amplify or attenuate the behavioural response. This constitutes a key advance in understanding how the brain decodes information inherent in patterns of nerve impulses, and provides insight into why the PSP has evolved to be so complex, and consequently why the phenotypes of synaptopathies are so diverse. Our most recent work has opened a new phase, and scale, in understanding synapses with the first synaptome maps of the brain. We have developed next-generation methods (SYNMAP) that enable single-synapse resolution molecular mapping across the whole mouse brain and extensive regions of the human brain, revealing the molecular and morphological features of a billion synapses. This has already uncovered unprecedented spatiotemporal synapse diversity organised into an architecture that correlates with the structural and functional connectomes, and shown how mutations that cause cognitive disorders reorganise these synaptome maps; for example, by detecting vulnerable synapse subtypes and synapse loss in Alzheimer’s disease. This innovative synaptome mapping technology has huge potential to help characterise how the brain changes during normal development, including in specific cell types, and with degeneration, facilitating novel pathways to diagnosis and therapy.

Growing Up in Academia with Christof Koch

Join us for a deep talk with Christof Koch, Chief Scientist of the MindScope Program, Allen Institute for Brain Science

Cross-modality imaging of the neural systems that support executive functions

Executive functions refer to a collection of mental processes such as attention, planning and problem solving, supported by a frontoparietal distributed brain network. These functions are essential for everyday life. Specifically in the context of patients with brain tumours there is a need to preserve them in order to enable good quality of life for patients. During surgeries for the removal of a brain tumour, the aim is to remove as much as possible of the tumour and at the same time prevent damage to the areas around it to preserve function and enable good quality of life for patients. In many cases, functional mapping is conducted during an awake surgery in order to identify areas critical for certain functions and avoid their surgical resection. While mapping is routinely done for functions such as movement and language, mapping executive functions is more challenging. Despite growing recognition in the importance of these functions for patient well-being in recent years, only a handful of studies addressed their intraoperative mapping. In the talk, I will present our new approach for mapping executive function areas using electrocorticography during awake brain surgery. These results will be complemented by neuroimaging data from healthy volunteers, directed at reliably localizing executive function regions in individuals using fMRI. I will also discuss more broadly challenges ofß using neuroimaging for neurosurgical applications. We aim to advance cross-modality neuroimaging of cognitive function which is pivotal to patient-tailored surgical interventions, and will ultimately lead to improved clinical outcomes.

What is Cognitive Neuropsychology Good For? An Unauthorized Biography

Abstract: There is no doubt that the study of brain damaged individuals has contributed greatly to our understanding of the mind/brain. Within this broad approach, cognitive neuropsychology accentuates the cognitive dimension: it investigates the structure and organization of perceptual, motor, cognitive, and language systems – prerequisites for understanding the functional organization of the brain – through the analysis of their dysfunction following brain damage. Significant insights have come specifically from this paradigm. But progress has been slow and enthusiasm for this approach has waned somewhat in recent years, and the use of existing findings to constrain new theories has also waned. What explains the current diminished status of cognitive neuropsychology? One reason may be failure to calibrate expectations about the effective contribution of different subfields of the study of the mind/brain as these are determined by their natural peculiarities – such factors as the types of available observations and their complexity, opportunity of access to such observations, the possibility of controlled experimentation, and the like. Here, I also explore the merits and limitations of cognitive neuropsychology, with particular focus on the role of intellectual, pragmatic, and societal factors that determine scientific practice within the broader domains of cognitive science/neuroscience. I conclude on an optimistic note about the continuing unique importance of cognitive neuropsychology: although limited to the study of experiments of nature, it offers a privileged window into significant aspects of the mind/brain that are not easily accessible through other approaches. Biography: Alfonso Caramazza's research has focussed extensively on how words and their meanings are represented in the brain. His early pioneering studies helped to reformulate our thinking about Broca's aphasia (not limited to production) and formalised the logic of patient-based neuropsychology. More recently he has been instrumental in reconsidering popular claims about embodied cognition.

Transdiagnostic approaches to understanding neurodevelopment

Macroscopic brain organisation emerges early in life, even prenatally, and continues to develop through adolescence and into early adulthood. The emergence and continual refinement of large-scale brain networks, connecting neuronal populations across anatomical distance, allows for increasing functional integration and specialisation. This process is thought crucial for the emergence of complex cognitive processes. But how and why is this process so diverse? We used structural neuroimaging collected from a large diverse cohort, to explore how different features of macroscopic brain organisation are associated with diverse cognitive trajectories. We used diffusion-weighted imaging (DWI) to construct whole-brain white-matter connectomes. A simulated attack on each child's connectome revealed that some brain networks were strongly organized around highly connected 'hubs'. The more children's brains were critically dependent on hubs, the better their cognitive skills. Conversely, having poorly integrated hubs was a very strong risk factor for cognitive and learning difficulties across the sample. We subsequently developed a computational framework, using generative network modelling (GNM), to model the emergence of this kind of connectome organisation. Relatively subtle changes within the wiring rules of this computational framework give rise to differential developmental trajectories, because of small biases in the preferential wiring properties of different nodes within the network. Finally, we were able to use this GNM to implicate the molecular and cellular processes that govern these different growth patterns.

Astrocytes contribute to remote memory formation by modulating hippocampal-cortical communication during learning

How is it that some memories fade in a day while others last forever? The formation of long-lasting (remote) memories depends on the coordinated activity between the hippocampus and frontal cortices, but the timeline of these interactions is debated. Astrocytes, star-shaped glial cells, sense and modify neuronal activity, but their role in remote memory is scarcely explored. We manipulated the activity of hippocampal astrocytes during memory acquisition and discovered it impaired remote, but not recent, memory retrieval. We also revealed a massive recruitment of cortical-projecting hippocampal neurons during memory acquisition, a process that is specifically inhibited by astrocytic manipulation. Finally, we directly inhibited this projection during memory acquisition to prove its necessity for the formation of remote memory. Our findings reveal that the foundation of remote memory can be established during acquisition with projection-specific effect of astrocytes.

A developmental-cognitive perspective on the impact of adolescent social media use

Concerns about the impact of social media use on adolescent well-being and mental health are common. While the amount of research in this area has increased rapidly over the last 5 years, most outputs are still marred by a multitude of limitations. These shortcomings have left our understanding of social media effects severely limited, holding back both scientific discovery and policy interventions. This talk discusses how developmental, cognitive and neuroscientific approaches might provide a new and improved way of studying social media effects. It will detail new studies in support of this idea, and raise potential avenues for collaborative work across the Cambridge Neuroscience community. As the digital world now (re)shapes what it means for us to live, communicate and develop, only an interdisciplinary approach will allow us to truly understand its impacts.

A generative n​etwork model of neurodevelopment

The emergence of large-scale brain networks, and their continual refinement, represent crucial developmental processes that can drive individual differences in cognition and which are associated with multiple neurodevelopmental conditions. But how does this organization arise, and what mechanisms govern the diversity of these developmental processes? There are many existing descriptive theories, but to date none are computationally formalized. We provide a mathematical framework that specifies the growth of a brain network over developmental time. Within this framework macroscopic brain organization, complete with spatial embedding of its organization, is an emergent property of a generative wiring equation that optimizes its connectivity by renegotiating its biological costs and topological values continuously over development. The rules that govern these iterative wiring properties are controlled by a set of tightly framed parameters, with subtle differences in these parameters steering network growth towards different neurodiverse outcomes. Regional expression of genes associated with the developmental simulations converge on biological processes and cellular components predominantly involved in synaptic signaling, neuronal projection, catabolic intracellular processes and protein transport. Together, this provides a unifying computational framework for conceptualizing the mechanisms and diversity of childhood brain development, capable of integrating different levels of analysis – from genes to cognition. (Pre-print: https://www.biorxiv.org/content/10.1101/2020.08.13.249391v1)

ALBA Webinar in Latin America: What are the main barriers to succeed in brain sciences in Latin America?

ALBA is launching a webinar series focusing on region-specific issues linked to diversity and faced by underrepresented groups in brain research around the world. In this first webinar, ALBA focus on issues linked to diversity and faced by underrepresented groups in brain research in Latin America.

Two pathways to self-harm in adolescence

The behavioural and emotional profiles underlying adolescent self-harm, and its developmental risk factors, are relatively unknown. The authors of this paper aimed to identify sub-groups of young people who self-harm (YPSH) and longitudinal predictors leading to self-harm using the Millennium Cohort Study. (Pre-print: https://www.medrxiv.org/content/10.1101/2020.07.10.20150789v1)

Contextual effects in the representation of complex sounds: from the inferior colliculus to higher-order cortical fields

Neuron-glia interactions in synapse degeneration in Alzheimer's disease

Tara Spires-Jones’ research focuses on the mechanisms and reversibility of neurodegeneration in Alzheimer’s disease, other degenerative brain diseases, and ageing.  The objective of her research group is to understand why synapses and neurons become dysfunctional and die in these diseases in order to develop effective therapeutic strategies. Her work has shown that soluble forms of the pathological proteins amyloid beta and tau contribute to synapse degeneration, and that lowering levels of these proteins can prevent and reverse phenotypes in model systems. Further, she has pioneered high-resolution imaging techniques in human post-mortem brain and found evidence that these proteins accumulate in synapses in human disease.