Neuroscience seminars

John DowlingJohn E. Dowling received his AB and PhD from Harvard University. He taught in the Biology Department at Harvard from 1961 to 1964, first as an Instructor, then as assistant professor. In 1964 he moved to Johns Hopkins University, where he held an appointment as associate professor of Ophthalmology and Biophysics. He returned to Harvard as professor of Biology in 1971, was the Maria Moors Cabot Professor of Natural Sciences from 1971-2001, Harvard College professor from 1999-2004 and is presently the Gordon and Llura Gund Professor of Neurosciences. Dowling was chairman of the Biology Department at Harvard from 1975 to 1978 and served as associate dean of the faculty of Arts and Sciences from 1980 to 1984. He was Master of Leverett House at Harvard from 1981-1998 and currently serves as president of the Corporation of The Marine Biological Laboratory in Woods Hole. He is a Fellow of the American Academy of Arts and Sciences, a member of the National Academy of Sciences and a member of the American Philosophical Society. Awards that Dowling received include the Friedenwald Medal from the Association of Research in Ophthalmology and Vision in 1970, the Annual Award of the New England Ophthalmological Society in 1979, the Retinal Research Foundation Award for Retinal Research in 1981, an Alcon Vision Research Recognition Award in 1986, a National Eye Institute's MERIT award in 1987, the Von Sallman Prize in 1992, The Helen Keller Prize for Vision Research in 2000 and the Llura Ligget Gund Award for Lifetime Achievement and Recognition of Contribution to the Foundation Fighting Blindness in 2001. He was granted an honorary MD degree by the University of Lund (Sweden) in 1982 and an honorary Doctor of Laws degree from Dalhousie University (Canada) in 2012. Dowling's research interests have focused on the vertebrate retina as a model piece of the brain. He and his collaborators have long been interested in the functional organization of the retina, studying its synaptic organization, the electrical responses of the retinal neurons, and the mechanisms underlying neurotransmission and neuromodulation in the retina. Dowling became interested in zebrafish as a system in which one could explore the development and genetics of the vertebrate retina about 20 years ago. Part of his research team has focused on retinal development in zebrafish and the role of retinoic acid in early eye and photoreceptor development. A second group has developed behavioral tests to isolate mutations, both recessive and dominant, specific to the visual system.

Real-time rendering of closed-loop visual environments is important for next-generation understanding of brain function and behaviour, but is often prohibitively difficult for non-experts to implement and is limited to few laboratories worldwide. We developed BonVision as an easy-to-use open-source software for the display of virtual or augmented reality, as well as standard visual stimuli. BonVision has been tested on humans and mice, and is capable of supporting new experimental designs in other animal models of vision. As the architecture is based on the open-source Bonsai graphical programming language, BonVision benefits from native integration with experimental hardware. BonVision therefore enables easy implementation of closed-loop experiments, including real-time interaction with deep neural networks, and communication with behavioural and physiological measurement and manipulation devices.

Large-scale, single neuron resolution recordings are inherently high-dimensional, with as many dimensions as neurons. To make sense of them, for many the answer is: reduce the number of dimensions. In this talk I argue we can distinguish weak and strong principles of neural dimension reduction. The weak principle is that dimension reduction is a convenient tool for making sense of complex neural data. The strong principle is that dimension reduction moves us closer to how neural circuits actually operate and compute. Elucidating these principles is crucial, for which we subscribe to provides radically different interpretations of the same dimension reduction techniques applied to the same data. I outline experimental evidence for each principle, but illustrate how we could make either the weak or strong principles appear to be true based on innocuous looking analysis decisions. These insights suggest arguments over low and high-dimensional neural activity need better constraints from both experiment and theory.

In an ever-changing environment, uncertainty is omnipresent. To deal with this, organisms have evolved mechanisms that allow them to take advantage of environmental regularities in order to make decisions robustly and adjust their behavior efficiently, thus maximizing their chances of survival. In this talk, I will present behavioral evidence that animals perform model-based state inference to predict environmental state changes and adjust their behavior rapidly, rather than slowly updating choice values. This model-based inference process can be described using Bayesian change-point models. Furthermore, I will show that neural populations in the prefrontal cortex accurately predict behavioral switches, and that the activity of these populations is associated with Bayesian estimates. In addition, we will see that learning leads to the emergence of a high-dimensional representational subspace that can be reused when the animals re-learn a previously learned set of action-value associations. Altogether, these findings highlight the role of the PFC in representing a belief about the current state of the world.

We must constantly adapt the rules we use to guide our attention. To understand how the brain learns these rules, we designed a novel task that required monkeys to learn which color is the most rewarded at a given time (the current rule). However, just as in real life, the monkey was never explicitly told the rule. Instead, they had to learn it through trial and error by choosing a color, receiving feedback (amount of reward), and then updating their internal rule. After the monkeys reached a behavioral criterion, the rule changed. This change was not cued but could be inferred based on reward feedback. Behavioral modeling found monkeys used rewards to learn the rules. After the rule changed, animals adopted one of two strategies. If the change was small, reflected in a small reward prediction error, the animals continuously updated their rule. However, for large changes, monkeys ‘reset’ their belief about the rule and re-learned the rule from scratch. To understand the neural correlates of learning new rules, we recorded neurons simultaneously from the prefrontal and parietal cortex. We found that the strength of the rule representation increased with the certainty about the current rule, and that the certainty about the rule was represented both implicitly and explicitly in the population.

Von Economo stated that an "Ideal Cortical Map" would look very different to a parcellation. He suggested that an Ideal Cortical Map would involve the superimposition of many different cortical maps, with changes in each map shown at every single point. In line with this idea, I will discuss our recent research on identifying principal dimensions of cortical differentiation. In particular, I will highlight large-scale patterns of cytoarchitectural differentiation that can be observed using post mortem histology or in vivo microstructure-sensitive MRI. I aim to show how this approach provides a cohesive framework to understand cortical organisation across multiple biological scales. This allows us to formulate new ideas on the organisation and function of the brain regions (eg: mesiotemporal lobe), networks (eg: DMN) and the whole cortex.

As Socrates said that "I know that I know nothing," our mind's function to be aware of our ignorance is essential for abstract and conceptual reasoning. However, the biological mechanism to enable such a hierarchical thought, or meta-cognition, remained unknown. In the first part of the talk, I will demonstrate our studies on the neural mechanism for metacognition on memory in macaque monkeys. In reality, awareness of ignorance is essential not only for the retrospection of the past but also for the exploration of novel unfamiliar environments for the future. However, this proactive feature of metacognition has been understated in neuroscience. In the second part of the talk, I will demonstrate our studies on the neural mechanism for prospective metacognitive matching among uncertain options prior to perceptual decision making in humans and monkeys. These studies converge to suggest that higher-order processes to self-evaluate mental state either retrospectively or prospectively are implemented in the primate neural networks.

Cluster headache is a brain disorder dominated clinically by dreadful episodes of excruciating pain with a circadian pattern and most often focused in bouts with circannual periodicity. As we have understood its neurobiology new therapies, including those directed at calcitonin gene-related peptide, are helpful improve the lives of sufferers.

PiVR is a system that allows experimenters to immerse small animals into virtual realities. The system tracks the position of the animal and presents light stimulation according to predefined rules, thus creating a virtual landscape in which the animal can behave. By using optogenetics, we have used PiVR to present fruit fly larvae with virtual olfactory realities, adult fruit flies with a virtual gustatory reality and zebrafish larvae with a virtual light gradient. PiVR operates at high temporal resolution (70Hz) with low latencies (<30 milliseconds) while being affordable (<US$500) and easy to build (<6 hours). Through extensive documentation (www.PiVR.org), this tool was designed to be accessible to a wide public, from high school students to professional researchers studying systems neuroscience in academia.

The ALBA Network is organizing a webinar on LGBTQIA+ inclusion and visibility. This special event will feature a panel of established scientists in brain research who identify as LGBTQIA+. Speaker will discuss their goals, challenges and successes while navigating academia as part of the LGBTQIA+ community. Registration is free but mandatory.

Pathogenic variants in HCN1 are associated with severe developmental and epileptic encephalopathies (DEE). We have engineered the Hcn1 M294L heterozygous knock-in (Hcn1M294L) mouse which is a homolog of the de novo HCN1 M305L recurrent pathogenic variant. The mouse recapitulates the phenotypic features of patients including having spontaneous seizures and a learning deficit. In this talk I will present experimental work that probes the molecular and cellular mechanisms underlying hyper-excitability in the mouse model. This will include testing the efficacy of currently available antiepileptic drugs and a novel precision medicine approach. I will also briefly touch on how disease biology can give insights into the biophysical properties of HCN channels.

Cerebral infection by the larvae of the cestode, Taenia solium (neurocysticercosis), is thought to be the leading cause of adult-acquired epilepsy worldwide. Despite this, little is known about the cellular mechanisms that underlie seizure development in this condition. In this talk I will present our recent data exploring multiple interactions between cestode larvae, neuroinflammatory processes and network excitability. We find that viable cestode larvae are able to strongly suppress microglial activation and inflammatory cytokine release with consequences for the modulation host neuroinflammatory responses and seizure development in vivo. At the same time, larvae produce and release glutamate, with acute excitatory effects on neuronal circuits. We hope that an improved understanding of epileptogenic mechanisms in neurocysticercosis will one day improve the management of this condition as well as other inflammatory causes of epilepsy.

Prosopometamorphopsia (PMO) is a disorder characterized by face perception distortions. People with PMO see facial features that appear to melt, stretch, and change size and position. I'll discuss research on PMO carried out by my lab and others that sheds light on the cognitive and neural organization of face perception. https://facedistortion.faceblind.org/

This seminar will focus on the extraordinary shift in migraine research during the last 4 decades with the discovery of the trigeminovascular system (TVS) and it’s major impact on pathophysiology and treatment. Compelling evidence supporting the importance of TVS, cortical spreading depression and parameningeal inflammation will be explored as will the implications of newly discovered microvascular channels within the meninges on an attack.

The CA1 pyramidal neurons are embedded in an intricate local circuitry that contains a variety of interneurons. The roles these interneurons play in the regulation of the excitatory synaptic plasticity remains largely understudied. Recent experiments showed that repeated cholinergic activation of 𝛼7 nACh receptors expressed in oriens-lacunosum-moleculare (OLM𝛼2) interneurons could induce LTP in SC-CA1 synapses. We used a biophysically realistic computational model to examine mechanistically how cholinergic activation of OLMa2 interneurons increases SC to CA1 transmission. Our results suggest that, when properly timed, activation of OLMa2 interneurons cancels the feedforward inhibition onto CA1 pyramidal cells by inhibiting fast-spiking interneurons that synapse on the same dendritic compartment as the SC, i.e., by disinhibiting the pyramidal cell dendritic compartment. Our work further describes the pairing of disinhibition with SC stimulation as a general mechanism for the induction of synaptic plasticity. We found that locally-reduced GABA release (disinhibition) paired with SC stimulation could lead to increased NMDAR activation and intracellular calcium concentration sufficient to upregulate AMPAR permeability and potentiate the excitatory synapse. Our work suggests that inhibitory synapses critically modulate excitatory neurotransmission and induction of plasticity at excitatory synapses. Our work also shows how cholinergic action on OLM interneurons, a mechanism whose disruption is associated with memory impairment, can down-regulate the GABAergic signaling into CA1 pyramidal cells and facilitate potentiation of the SC-CA1 synapse.