Talk followed by coffee and cake

Follows talk by Prof. Shoi Shi

Talk followed by Pub Social at the King’s Arms

THIS TALK HAS BEEN CANCELLED DUE TO ILLNESS

Title

The MAST Proteins in Neurodevelopment and Disease

Abstract

The microtubule cytoskeleton plays an indispensable role in building the vertebrate central nervous system. Microtubules mediate the separation of sister chromatids during mitosis, they provide the force to translocate the nucleus in migrating neurons, and they are critical for axon extension as neurons differentiate. This talk focuses on an uncharacterised family of Microtubule Associated Serine Threonine (MAST) Kinases, and how mutations in this gene family cause a spectrum of neurological phenotypes, most notably mega corpus callosum syndrome.

Sign up to join Prof Keays for lunch! https://docs.google.com/forms/d/1bH-lX6DBB_smu-VQcOkXw9gidg9mHivd61CyhqZwXZc/edit

Title:

Neural Circuits of Kinship Behaviour

Abstract:

Evolutionary theory and behavioral biology suggest that kinship is an organizing principle of social behavior. The neural mechanisms that mediate kinship behavior are, however, not known. Experiments confirm a sibling-approach preference in young rat pups and a sibling-avoidance-preference in older pups. Lesions of the lateral septum eliminate such kin preferences. In vivo juxta-cellular and whole-cell patch-clamp recordings in the lateral septum show multisensory neuronal responses to kin and non-kin stimuli. Non-kin odor-responsive neurons are located dorsally and kin-odor responsive neurons are located ventrally in the lateral septum. With development, the fraction of kin-responsive lateral septal neurons decrease and ongoing firing rates increase. Lesion effects, developmental changes and the ordered representation of response preferences according to kinship—an organization we refer to as nepotopy—point to a key role of the lateral septum in organizing mammalian kinship behavior.

Lunch sign-up form:

https://docs.google.com/forms/d/e/1FAIpQLSdGnGyrRUjinbFyZsIhpOLSNvhfMjzba6WOglSwxebNsxICOA/viewform

Title:

Flexible neuronal mitochondrial dynamics control sleep

Abstract:

Sleep is vital and universal, but the underlying mechanisms that drive and control it remain elusive. In essence, the neural control of sleep requires that sleep need is sensed during waking and discharged during sleep. In Drosophila, sleep deprivation leads to the accumulation of reactive oxygen species (ROS) in the mitochondria of sleep-control neurons projecting to the dorsal fan-shaped body (dFB). This internal representation of sleep need is then translated into sleep via increased excitability of these neurons by the redox-sensitive β-subunit of the voltage-gated potassium channel Shaker.

The unknown signalling cascades transducing sleep pressure (tracked by ROS levels) to sleep (via increased excitability) must thus entail rearrangements of the mitochondrial machinery.To obtain a comprehensive view of the cellular and molecular arsenal operating within dFB neurons, we characterised transcriptomes of single cells isolated from brains of rested and sleep-deprived flies.
Sleep deprivation selectively upregulated genes encoding mitochondrial proteins, and was accompanied by reversible morphological changes indicating organelle fragmentation.

Likewise, artificially inducing mitochondrial fragmentation or fusion in dFB neurons affected their electrical properties and sleep in opposing ways: hyperfused mitochondria increased neural excitability and sleep duration, while fragmented mitochondria led to the opposite changes. Since mitochondrial dynamics reflect and influence ATP levels, we measured the cellular ATP content and found that it increased with sleep drive. Conversely, tuning the ATP content by dissipating the mitochondrial proton-motive force specifically in dFB neurons diminished sleep. Moreover, addition of ATP in neurons with fragmented mitochondria rescued their blunted excitability. Since mitochondrial dynamics and ATP are linked to ROS production, our study suggests a causal and bidirectional link between cellular bioenergetics and excitability of sleep-control neurons. Our first single-cell transcriptome of an animal’s sleep-control neurons in different conditions of sleep pressure will help to elucidate the physiological variables that are linked to the essential function of sleep.

Title:

Circuit and single neuron computations for flexible decision-making

Abstract:

Making flexible decisions in a dynamic environment is a powerful capacity of the mammalian brain. Despite decades of research at the behavioral and cognitive levels, the biological mechanisms implementing computations underlying flexible decision-making remain largely unknown. Here we developed an inferece-based flexible decision-making task in mice and combined in vivo two-photon imaging, large-scale neurophysiological recording and circuit manipulations to investigate the underlying neuronal mechanisms. Using cross-brain region circuit analysis, we show that the orbitofrontal-sensory cortical circuits implement an inference-based algorithm conferring a high degree of flexibility in rule-switching behavior. Using subcelullar two-photon imaging, we found that layer 5 cortical pyramidal neurons compartementalize different types of task information in dendritic and somatic subcellular domains, suggesting a dendritic integration mechanism for rule-based decisions. Using brain-wide electrophysiology, we further show that the representations for task variables of different degree of abstraction are orderly distributed across hierarchical brain regions. Our results provide new insights to the neuronal and circuit mechanisms implementing biological algorithms for flexible decision-making.

Talk title
Computational analysis of microcircuit mechanisms supporting hippocampal dynamics

Abstract
Understanding how brain architecture and neural coordination generate different processing strategies is one of the greatest challenges of neuroscience. The goal of our work is to develop different computational strategies to understand the mechanisms by which hippocampal neural circuits process information across multiple levels. In this talk, I will discuss how the interaction of circuit, synaptic, and intrinsic neuronal properties determine firing preferences during learning, and how this neural activity forms population wide brain rhythms. We demonstrate how perisomatic inhibition interacts with different input pathways to shape in vivo activity of specific pyramidal neuron populations; how place field generation is best explained by a disinhibitory process; and demonstrate how detection and analysis of hippocampal dynamical activity using feature-based approaches can lead to deeper insights of the underlying neural activity. Together, we showed how advanced computational techniques such as modelling, evolutionary algorithms and artificial intelligence approaches can enhance our understanding of neural circuit processing.

Talk title

Probing economic decision preferences in mice

Abstract

Real life decisions often occur in volatile environments and require strategic interaction between multiple decision makers. These external variables interact with our internal states and past experience, resulting in individual differences in decision preference, even when faced with identical sensory information. Imagine decisions at a poker table or foraging decisions in a competitive, changing environment. In both situations, animals make decisions based on incomplete information, under risk and uncertainty, and in a social context. Also, in both situations, the optimal strategy requires stochastic choices. Due to the multiplexed and dynamic nature of these types of decisions, there are usually no uniquely correct answers. Instead, choices reflect individuals’ varied decision preferences that lead to differential short-term and long-term gains. Our goal is to understand how animals make flexible decisions under risk and social influence, and the neural circuit mechanisms underlying these choices. Towards this goal, we plan to combine theory-motivated behavioural designs, quantitative extraction of animals’ internal states, large-scale, cellular-resolution monitoring and manipulation of brain activity during decision tasks, and computational modelling. In this talk, I will outline our lab’s vision, our approaches towards these goals, and preliminary progress over the past 1.5 years of my lab.

Student Brunch: please join us for a brunch with Prof Ann Duan in the Sherrington Library at 11 am - sign up here!

Talk title

Subcellular Molecular Machinery for Circuit-Specific Brain Wiring, Disease, and (potentially) Regeneration: Distinct and Dynamic Growth Cone vs. Soma RNA and Local Translational Regulation in Cerebral Cortex Projection Neurons

Abstract

The long-term goals of the work I will discuss are three-fold – in development, disease, and regeneration: 1) to elucidate central molecular mechanisms controlling development and diversity of cerebral cortex function-specific circuitry, thus organization and evolution (to some extent) of the cerebral cortex; 2) to identify causes/mechanisms of developmental and selective neuron subtype vulnerability in many neurodegenerative disorders; and 3) to elucidate and potentially overcome blocks to CNS regeneration. The specificity, modification, and function of such circuitry underlies how the brain-nervous system senses, integrates, moves the body, thinks, functions with precision, malfunctions with specificity in disease, degenerates with circuit specificity, might be regenerated, and/or might be modeled in culture, but has been previously inaccessible in multiple core aspects. What actually implements and maintains circuit specificity is a key, core issue from developmental specificity of circuits, to developmental abnormalities and disease, proper function (or dysfunction) and circuit type-specific molecular regulators and drugs, selective neuron type vulnerability of degeneration (e.g. in MND/ALS, Huntington’s, Parkinson’s diseases), regeneration (or typical lack thereof) in the CNS for spinal cord injury, and mechanistic and therapeutic modeling of disease using human induced pluripotent stem cell (hiPS)-derived neurons. Growth cones (GCs) are the subcellular structures that “build” circuits with specificity and mature into synapses, where human genomic risk associations are showing up in neuropsychiatric diseases such as schizophrenia, autism, bipolar disorder, developmental intellectual disabilities, but we know little about the diversity and specialization of circuit-specific GCs or synapses. I will present a brief integration of recent work investigating subtype-, stage-, and target-specific GCs and synapses in development, neuronal and circuit diversity, disease, regeneration, and newly enabled hiPS-based fused organoid “assembloids” to address these critical gaps in knowledge. I will dabble a bit in discussing evolution here and there. We have developed and integrate several new approaches (e.g. subtype- and stage-specific subcellular RNA, protein, translational regulation, “specialized” ribosome analysis of GCs / synapses directly from brains; mosaic genetic circuit analysis; hiPS “assembloids” with somewhat selective connectivity) to investigate basic “framing rules” of diverse function-enabling CNS circuitry, potentially explain selective vulnerability in developmental and degenerative nervous system diseases, and potentially enable CNS regeneration.

Talk Title

A unique coding of memories in the human brain

Abstract

I will describe single neuron recordings in the human hippocampal formation and how neurons in this area form and store memories. I will also discuss how the coding by these neurons is completely different to what has been described in other species, challenging the notion of pattern separation.

For students

We are organising a student lunch with Prof Quiroga from 13:30-14:30 in the Sherrington Library (DPAG). Please sign up here if you would like to attend.

For postdocs/PIs

We can arrange for the possibility of meeting with Prof. Quiroga 1:1 throughout the day. Please contact demi.brizee@bndu.ox.ac.uk if you are interested.

Talk Title:

The Origins of Stereoscopic Vision

Abstract:

Full stereoscopic vision entails seeing objects in depth using both eyes. This talk will review the emergence of different types of binocular vision in a variety of species. Redundancy reduction appears as an important principle that shapes the initial binocular representation of inputs from the two eyes. This first step provides advantages in visual processing above and beyond the simple reduction of noise by combining signals from the two eyes. In primates, the rest of binocular processing appears to be built on this platform.

We will close this academic year with a workshop from DPAG Professor Randy Bruno (University of Oxford). Everything you ever want to know but were afraid to ask about neuronal electrophysiology, this workshop is your chance! And, if that is not enough to sign up already, complimentary pizzas will be on us! Please sign-up here.

Topic of Workshop:

Electrophysiological recordings of neurons

Together with the Oxford University Society of Biomedical Sciences (OUSBMS), we are co-organising a talk by Prof Rafal Bogacz at the end of this Michaelmas term. Tickets are usually £3 for non-members of the OUSBMS, but any member of the Cortex Club can attend for free (just show one of our emails to demonstrate membership). There will be snacks, drinks and Prosecco!

Talk Title:

Models of Reinforcement Learning in the Brain

Abstract:

This talk will illustrate how computational models can be useful in understanding cognitive functions of the brain. It will focus on reinforcement learning models that have provided an elegant mechanistic description for how neural circuits in the basal ganglia can learn about expected reward. The presentation will start with an overview of classical models proposing that dopaminergic activity encodes prediction errors that drive learning. Then it will discuss a recent model of how the basal ganglia also learn about different dimensions of reward (e.g. food and water). The talk will illustrate that formal theory in neuroscience can be used to interpret data and generate predictions for new experiments, analogously as in more mature scientific disciplines.

**TIME, DATE AND LOCATION CHANGED**

Talk title:

Cellular and synaptic microcircuit principles of the human cortical layer 2-3

Abstract:

In the brain, information processing is defined by the properties of neurons and their interaction via structured synaptic connections. In the human cortex layer 2-3, recent studies have uncovered a greater pyramidal neuron diversity and divergent synaptic properties compared to rodents. However, to what extent these synaptic properties are related to cellular heterogeneity and how connectivity is structured in the human cortex is unknown.
In this talk, I will present unpublished data on 1214 electrophysiologically characterized pyramidal neurons and 1419 identified monosynaptic connections from 23 individuals. Using multi-neuron patch-clamp recordings, we observed functional subtypes in the human cortical layer 2-3 that exhibited substantial heterogeneity in their cellular and synaptic function within single individuals. We further identified multiple network principles that are in stark contrast to previous rodent studies, suggesting a directed and mostly acyclic graph topology of the human cortical microcircuit. Analysis and simulation of neural network models applying these wiring principles showed an increased dimensionality of network dynamics and improved performance in a speech recognition task. Taken together, our cellular and synaptic data attributes the human cortical microcircuit with the capacity for high-dimensional neural computation.

Title:

Optogenetic dissection of local and long-range connections in prefrontal circuits

Abstract:

The prefrontal cortex (PFC) plays an important role in regulating social functions in mammals, and impairments in this region have been linked with social dysfunction in psychiatric disorders. The PFC plays a part in multiple brain-wide networks regulating behavior, and its long-range connections to different cortical and subcortical targets are thought to be involved in distinct behavioral functions. How is information about the multitude of cognitive/behavioral processes routed into and out of the PFC circuit? We are interested in understanding how PFC microcircuits process behavioral information, and how distinct PFC output neuron populations regulate learning, decision-making and social behavior.

I will first describe a set of experiments aimed at understanding the structure of synaptic connectivity among amygdala-projecting neurons in the mPFC. Using single-neuron twophoton optogenetic stimulation and imaging, we demonstrated that these neurons form unique connectivity modules in the deep and superficial layers of the mPFC. I will then describe our efforts to engineer new optogenetic tools for silencing of long-range axonal projections between brain regions. To efficiently suppress synaptic transmission, we engineered a new set of rhodopsin-based optogenetic tools that selectively couple to the Gi/o signaling pathway and strongly suppress synaptic release in vitro and in vivo.

Talk title:

Detecting covert decision dynamics from neural population recordings in primate motor cortex

Abstract:

The neural mechanisms underlying decision-making are typically inferred from the average activity from sequentially recorded single neurons, which obscures important aspects of decision-making dynamics. I will show that covert decision variables (DV) can be tracked dynamically on single behavioral trials via simultaneous recording of large neural populations in primate motor cortex. I will also show—in nonhuman primates under the conditions of our experiments—that decisions are encoded by relatively stationary populations of neurons, not by sequences of activity passed from neuron-to-neuron.

Speaker: Janos Szabadics (KOKI: Institute of Experimental Medicine, Hungary)

Title: Compensating potassium conductance maintains uniform action potential shape along individual axons with variable calibre in hippocampus

Abstract: The axonal diameter varies within individual axons. There are smaller and larger boutons along the thin axonal trunk. This morphological diversity is also reflected by the biophysical environment, as the smaller diameter means smaller capacitance and typically larger input resistance. The local biophysical environment influences spike shapes, which is the most important neuronal output signal. For example, wider action potentials usually result in more reliable and larger synaptic responses. Therefore, the variability of axonal size can make axonal signalling quite complex because each synapse would see a different dynamic signal. To address how axons handle this issue we used direct patch clamp recording and voltage imaging from small and large mossy fibres and axons originating from the supramammillary nucleus in the hippocampus. The results revealed that the amplitudes and shapes of the APs were surprisingly similar within the same type of axons, regardless of the axonal thickness. Thus, despite the different local biophysical environments, variable diameter axons actively maintain uniform action potential shapes. Outside out patch recordings of the isolated currents and pharmacological evidence suggest that smaller axons utilize more potassium currents to accelerate action potentials relative to larger axon segments. Specifically, the contribution of Kv1 channels is more prominent in smaller diameter axons than in larger boutons. Thus, we conclude that uniform AP shape is actively maintained within the same type of axons and axons provide similar digital signals to each of their synapses for maintaining output.

An informal social will follow with drinks offered by the society!

Speaker: Dr Hayriye Cagnan (Oxford, UK)

Title: Stimulating at the right time

Abstract: Stimulation-based therapies for brain disorders provide an exciting avenue due to their focal and reversible nature. Current approaches face limits of side-effects, and effectiveness being restricted to a small subset of the patient population. During this talk, I will highlight our recent work on developing and testing new therapies that aim to overcome these challenges. We approach this problem from multiple angles and use theoretical modelling, bioengineering, clinical electrophysiology, and neuroimaging.

An informal social will follow!