Neuroscience seminars

Although electroencephalography (EEG) has been used in clinical and research studies for almost a century, recent technological advances have made the equipment and processing tools more accessible outside laboratory settings. These low-cost alternatives can achieve satisfactory results in experiments such as detecting event-related potentials and classifying cognitive states. In our research, we use low-cost single-channel EEG to classify brain activity during the presentation of images of opposite emotional valence from the OASIS database. Emotional classification has already been achieved using research-grade and commercial-grade equipment, but our approach pioneers the use of educational-grade equipment for said task. EEG data is collected with a Backyard Brains SpikerBox, a low-cost and open-source bioamplifier that can record a single-channel electric signal from a pair of electrodes placed on the scalp, and used to train machine learning classifiers.

Seizures can emerge from multiple or large foci in temporal lobe epilepsy (TLE), complicating focally targeted strategies such as surgical resection or the modulation of the activity of specific hippocampal neuronal populations through genetic or optogenetic techniques. Here, we evaluate a strategy in which optogenetic activation of medial septal GABAergic neurons (MSGNs), which provide extensive projections throughout the hippocampus, is used to control seizures. We found that MSGNs were structurally and functionally resilient in the chronic intrahippocampal kainate mouse model of TLE, which as is often the case in human TLE patients, presents with hippocampal sclerosis. Optogenetic stimulation of MSGNs modulated oscillations across the rostral to caudal extent of the hippocampus in epileptic conditions. Chronic wireless optogenetic stimulation of MSGNs, upon electrographic detection of spontaneous hippocampal seizures, resulted in reduced seizure durations. We propose MSGNs as a novel target for optogenetic control of seizures in TLE.

The Georgia Tech Brain Music Lab is a community gathered around a unique facility combining EEG and other physiological measurement techniques with new music technologies. Their mission is to engage in research and creative practice that brings health and well-being. This talk will present an overview of the activities at the Brain Music Lab, including sonification of physiological signals, acoustic design for health and well-being, therapeutic applications of musical stimulation, and brain-body music performance.

In many ways, cognitive neuroscience is the attempt to use physiological observation to clarify the mechanisms that shape behavior. Over the past 25 years, fMRI has provided a system-wide and yet somewhat spatially precise view of the response in human cortex evoked by a wide variety of stimuli and task contexts. The current talk focuses on the other direction of inference; the implications of this observed functional organization for behavior. To begin, we must interrogate the methodological and empirical frameworks underlying our derivation of this organization, partially by exploring its relationship to and predictability from gross neuroanatomy. Next, across a series of studies, the implications of two properties of functional organization for behavior will be explored: 1) the co-localization of visual working memory and perceptual processing and 2) implicit learning in the context of distributed responses. In sum, these results highlight the limitations of our current approach and hint at a new general mechanism for explaining observed behavior in context with the neural substrate.

Organisms sense light for purposes that range from recognizing objects to synchronizing activity with environmental cycles. What mechanisms serve these diverse tasks? This seminar will examine the specializations of two cell types. First are the foveal cone photoreceptors. These neurons are used by primates to see far greater detail than other mammals, which lack them. How do the biophysical properties of foveal cones support high-acuity vision? Second are the melanopsin retinal ganglion cells, which are conserved among mammals and essential for processes that include regulation of the circadian clock, sleep, and hormone levels. How do these neurons encode light, and is encoding customized for animals of different niches? In pursuing these questions, a broad goal is to learn how various levels of biological organization are shaped to behavioural needs.

Genome-wide association studies implicate microglia in Alzheimer’s disease (AD) pathogenesis, but how microglia contribute to cognitive decline in AD is unclear. Emerging research suggests microglia, the resident macrophages of the central nervous system, to be active participants in brain wiring. One mechanism by which microglia help eliminate synapses is through the classical complement pathway (C1q, CR3/C3). Data from multiple laboratories collectively suggest that there may be an aberrant reactivation of the complement-dependent pruning pathway in multiple models of neurologic diseases including AD. These data altogether suggest that microglia participate in synaptic pathology. However, how and which synapses are targeted are unknown. Furthermore, whether microglia directly impair synaptic function is unknown. Primary goals of my laboratory are to understand how higher cognitive functions such as learning and memory involve microglial biology in the healthy adult brain and dissect immune mechanisms behind the region-specific vulnerability of synapse loss and neuronal dysfunction during disease. Mechanistic insight into local signals that regulate neuroglia interactions will be key to developing potential therapeutic avenues to target in disease.

Temporal lobe epilepsy is associated with memory deficits but the circuit mechanisms underlying these cognitive disabilities are not understood. We used electrophysiological recordings, open-source wire-free miniaturized microscopy and computational modeling to probe these deficits in a model of temporal lobe epilepsy. We find desynchronization of dentate gyrus interneurons with CA1 interneurons during theta oscillations and a loss of precision and stability of place fields. We also find that emergence of place cell dysfunction is delayed, providing a potential temporal window for treatments. Computation modeling shows that desynchronization rather than interneuron cell loss can drive place cell dysfunction. Future studies will uncover cell types driving these changes and transcriptional changes that may be driving dysfunction.

People frequently interpret the same information differently, based on their prior beliefs and views. This may occur in everyday settings, as when two friends are watching the same movie, but also in more consequential circumstances, such as when people interpret the same news differently based on their political views. The role of subjective knowledge in altering how the brain processes narratives has been explored mainly in controlled settings. I will present two projects that examines neural mechanisms underlying narrative interpretation “in the wild” -- how responses differ between two groups of people who interpret the same narrative in two coherent, but opposing ways. In the first project we manipulated participant’s prior knowledge to make them interpret the narrative differently, and found that responses in high-order areas, including the default mode network, language areas and subsets of the mirror neuron system, tend to be similar among people who share the same interpretation, but different from people with an opposing interpretation. In contrast to the active manipulation of participants’ interpretation in the first study, in the second (ongoing) project we examine these processes in a more ecological setting. Taking advantage of people’s natural tendencies to interpret the world through their own (political) filters, we examine these mechanisms while measuring their brain response to political movie clips. These studies are intended to deepen our understanding of the differences in subjective construal processes, by mapping their underlying brain mechanisms.

Over the past decade, the domain of face identity processing has seen a surging interest in inter-individual differences, with a focus on individuals with superior skills, so-called Super-Recognizers (SRs; Ramon et al., 2019; Russell et al., 2009). Their study can provide valuable insights into brain-behavior relationships and advance our understanding of neural functioning. Despite a decade of research, and similarly to the field of developmental prosopagnosia, a consensus on diagnostic criteria for SR identification is lacking. Consequently, SRs are currently identified either inconsistently, via suboptimal individual tests, or via undocumented collections of tests. This state of the field has two major implications. Firstly, our scientific understanding of SRs will remain at best limited. Secondly, the needs of government agencies interested in deploying SRs for real-life identity verification (e.g., policing) are unlikely to be met. To counteract these issues, I suggest the following action points. Firstly, based on our and others’ work suggesting novel and challenging tests of face cognition (Bobak et al., 2019; Fysh et al., in press; Stacchi et al., 2019), and my collaborations with international security agencies, I recommend novel diagnostic criteria for SR identification. These are currently being used to screen the Berlin State Police’s >25K employees before identifying SRs via bespoke testing procedures we have collaboratively developed over the past years. Secondly, I introduce a cohort of SRs identified using these criteria, which is being studied in-depth using behavioral methods, psychophysics, eye-tracking, and neuroimaging. Finally, I suggest data acquired for these individuals should be curated to develop and share best practices with researchers and practitioners, and to gain an accurate and transparent description of SR cases to exploit their informative value.

The hippocampus is implicated in memory formation, and neurons in the hippocampus take part in replay sequences, time-compressed reactivations of trajectories through space the animal has previously explored. These replay sequences have been proposed to be a form of memory for previously experienced places. I will present work exploring how these replays appear and change with experience. By recording from large ensembles of hippocampal neurons as rats explored novel and familiar linear tracks in various experiments, we found that hippocampal replays appear after a single experience and slow down with subsequent experience as greater detail is incorporated. We also investigated hover-and-jump dynamics within replays that are associated with the slow gamma (25-50Hz) oscillation in the LFP and found that replays slow down by adding more hover locations, corresponding to depiction of the behavioral trajectory with increased resolution. Thus, replays can reflect single experiences, and be rapidly modified by subsequent experience to incorporate more detail, consistent with their proposed role as a basic mechanism of hippocampally dependent memory.

Human genes associated with brain-related diseases are being discovered at an accelerating pace. A major challenge is an identification of the mechanisms through which these genes act, and of potential therapeutic strategies. To elucidate such mechanisms in human cells, we established a CRISPR-based platform for genetic screening in human iPSC-derived neurons, astrocytes and microglia. Our approach relies on CRISPR interference (CRISPRi) and CRISPR activation (CRISPRa), in which a catalytically dead version of the bacterial Cas9 protein recruits transcriptional repressors or activators, respectively, to endogenous genes to control their expression, as directed by a small guide RNA (sgRNA). Complex libraries of sgRNAs enable us to conduct genome-wide or focused loss-of-function and gain-of-function screens. Such screens uncover molecular players for phenotypes based on survival, stress resistance, fluorescent phenotypes, high-content imaging and single-cell RNA-Seq. To uncover disease mechanisms and therapeutic targets, we are conducting genetic modifier screens for disease-relevant cellular phenotypes in patient-derived neurons and glia with familial mutations and isogenic controls. In a genome-wide screen, we have uncovered genes that modulate the formation of disease-associated aggregates of tau in neurons with a tauopathy-linked mutation (MAPT V337M). CRISPRi/a can also be used to model and functionally evaluate disease-associated changes in gene expression, such as those caused by eQTLs, haploinsufficiency, or disease states of brain cells. We will discuss an application to Alzheimer’s Disease-associated genes in microglia.

David Chalmers’s (1995) hard problem famously states: “It is widely agreed that experience arises from a physical basis, but we have no good explanation of why and how it so arises.” Thomas Nagel (1974) wrote something similar: “If we acknowledge that a physical theory of mind must account for the subjective character of experience, we must admit that no presently available conception gives us a clue about how this could be done.” This presentation will point the way towards the long-sought “good explanation” -- or at least it will provide “a clue”. I will make three points: (1) It is unfortunate that cognitive science took vision as its model example when looking for a ‘neural correlate of consciousness’ because cortical vision (like most cognitive processes) is not intrinsically conscious. There is not necessarily ‘something it is like’ to see. (2) Affective feeling, by contrast, is conscious by definition. You cannot feel something without feeling it. Moreover, affective feeling, generated in the upper brainstem, is the foundational form of consciousness: prerequisite for all the higher cognitive forms. (3) The functional mechanism of feeling explains why and how it cannot go on ‘in the dark’, free of any inner feel. Affect enables the organism to monitor deviations from its expected self-states in uncertain situations and thereby frees homeostasis from the limitations of automatism. As Nagel says, “An organism has conscious mental states if and only if there is something that it is like to be that organism—something it is like for the organism.” Affect literally constitutes the sentient subject.

Understanding what drives foraging decisions in animals requires careful manipulation of the value of available options while monitoring animal choices. Value-based decision-making tasks, in combination with formal learning models, have provided both an experimental and theoretical framework to study foraging decisions in lab settings. While these approaches were successfully used in the past to understand what drives choices in mammals, very little work has been done on fruit flies. This is even though fruit flies have served as a model organism for many complex behavioural paradigms. To fill this gap we developed a single-animal, trial-based decision-making task, where freely walking flies experienced optogenetic sugar-receptor neuron stimulation. We controlled the value of available options by manipulating the probabilities of optogenetic stimulation. We show that flies integrate a reward history of chosen options and forget value of unchosen options. We further discover that flies assign higher values to rewards experienced early in the behavioural session, consistent with formal reinforcement learning models. Finally, we show that the probabilistic rewards affect walking trajectories of flies, suggesting that accumulated value is controlling the navigation vector of flies in a graded fashion. These findings establish the fruit fly as a model organism to explore the genetic and circuit basis of value-based decisions.

I will present work on a novel fMRI analysis method that allows us to investigate sequential reactivation in the hippocampus. Our method focuses on analysing the time courses of probabilistic multivariate classifiers and allows us to infer the presence and frequency of fast sequential reactivation events. Using a paradigm in which we controlled the speed of sequential visually elicited activations, we validated the method in visual cortex for event sequences with only 32 ms between items. We show that detectability remains possible if low signal-to-noise ratio and when sequence events occur at unknown times. In a preliminary analysis, we show that even the exposure to our visual paradigm elicits reactivations in visual cortex at rest following the task. I then present work in which we tested how representations influence replay by asking whether transitions between task-state representations are reactivated at rest during hippocampal replay events. Participants learned to make decisions about ambiguous stimuli that depended on past events and attentionally filtered stimulus processing. FMRI signals during rest periods following this task indicated sequential reactivation of task states. These results indicate that adaptive task state representations are computed and replayed at different cortical sites. In combination with other methods, fMRI may allow us to unravel this coordinated nature of replay.

How does the presence or absence of food shape and prioritize behavioral decisions? When is food more than just food? As in other animals, prolonged food deprivation dramatically alters sensory behaviors in C. elegans. For instance, it has been known since the mid-1970s that hungry worms no longer respond to temperature changes in their environment, but the underlying mechanisms have been unclear. I will describe unpublished work showing that insulin signaling from the gut regulates thermosensory behaviors as a function of feeding state by engaging a modulatory sensorimotor circuit that gates the output of the core thermosensory network. C. elegans is associated with, and consumes, diverse bacteria in the wild. I will also discuss a recent story in which we find that in addition to providing nutrition, a bacterial strain in the worm gut alters the hosts’ olfactory behavior and drives food choice decisions by producing a neurotransmitter that targets the hosts’ sensory neurons. These results add to our growing body of knowledge of how signaling from the gut modulates peripheral and central neuron properties and drives sensory behavioral plasticity.

In this talk, Dr Singleton will discuss the progress made so far in understanding the genetic basis of Parkinson’s disease. He will cover the history of discovery from the first identification of disease causing mutations to the state of knowledge in the field today, more that 20 years after that initial discovery. He will then discuss current initiatives and the promise of these for informing the understanding and treatment of Parkinson’s disease. Lastly, Dr Singleton will talk about current gaps in research and knowledge and working together to fill these.