Brain-Wide Compositionality and Learning Dynamics in Biological Agents

Biological agents continually reconcile the internal states of their brain circuits with incoming sensory and environmental evidence to evaluate when and how to act. The brains of biological agents, including animals and humans, exploit many evolutionary innovations, chiefly modularity—observable at the level of anatomically-defined brain regions, cortical layers, and cell types among others—that can be repurposed in a compositional manner to endow the animal with a highly flexible behavioral repertoire. Accordingly, their behaviors show their own modularity, yet such behavioral modules seldom correspond directly to traditional notions of modularity in brains. It remains unclear how to link neural and behavioral modularity in a compositional manner. We propose a comprehensive framework—compositional modes—to identify overarching compositionality spanning specialized submodules, such as brain regions. Our framework directly links the behavioral repertoire with distributed patterns of population activity, brain-wide, at multiple concurrent spatial and temporal scales. Using whole-brain recordings of zebrafish brains, we introduce an unsupervised pipeline based on neural network models, constrained by biological data, to reveal highly conserved compositional modes across individuals despite the naturalistic (spontaneous or task-independent) nature of their behaviors. These modes provided a scaffolding for other modes that account for the idiosyncratic behavior of each fish. We then demonstrate experimentally that compositional modes can be manipulated in a consistent manner by behavioral and pharmacological perturbations. Our results demonstrate that even natural behavior in different individuals can be decomposed and understood using a relatively small number of neurobehavioral modules—the compositional modes—and elucidate a compositional neural basis of behavior. This approach aligns with recent progress in understanding how reasoning capabilities and internal representational structures develop over the course of learning or training, offering insights into the modularity and flexibility in artificial and biological agents.

Irisin reduces amyloid-β by inducing the release of neprilysin from astrocytes following downregulation of ERK-STAT3 signaling

Circuit mechanisms of attention dysfunction in Scn8a+/- mice: implications for epilepsy and neurodevelopmental disorders

Nociceptor neurons direct goblet cells via a CGRP-RAMP1 axis to drive mucus production and gut barrier protection

Visual Perception in Cerebral Visual Impairment (CVI)

The impact of emerging technologies and methods on the interpretation of genetic variation in autism and fetal genomics

Mechanisms and Roles of Fast Dopamine Signaling

Dopamine is a neuromodulator that codes information on various time scales. I will discuss recent progress on the identification of fast release mechanisms for dopamine in the mouse striatum. I will present data on triggering mechanisms of dopamine release and evaluate its roles in striatal regulation. In the long-term, our work will allow for a better understanding of the mechanisms and time scales of dopamine coding in health and disease.

Transcriptional adaptation couples past experience and future sensory responses

Animals traversing different environments encounter both stable background stimuli and novel cues, which are generally thought to be detected by primary sensory neurons and then distinguished by downstream brain circuits. Sensory adaptation is a neural mechanism that filters background by minimizing responses to stable sensory stimuli, and a fundamental feature of sensory systems. Adaptation over relatively fast timescales (milliseconds to minutes) have been reported in many sensory systems. However, adaptation to persistent environmental stimuli over longer timescales (hours to days) have been largely unexplored, even though those timescales are ethologically important since animals typically stay in one environment for hours. I showed that each of the ~1,000 olfactory sensory neuron (OSN) subtypes in the mouse harbors a distinct transcriptome whose content is precisely determined by interactions between its odorant receptor and the environment. This transcriptional variation is systematically organized to support sensory adaptation: expression levels of many genes relevant to transforming odors into spikes continuously vary across OSN subtypes, dynamically adjust to new environments over hours, and accurately predict acute OSN-specific odor responses. The sensory periphery therefore separates salient signals from predictable background via a transcriptional mechanism whose moment-to-moment state reflects the past and constrains the future; these findings suggest a general model in which structured transcriptional variation within a cell type reflects individual experience.

Artisans of brain wiring: neuron-microglia selective crosstalk in brain wiring and function

Neural cartography: Mapping the brain with X-ray and electron microscopy

Neurobiology of Narcolepsy: effects of the oxytocin system on cataplexy

Selectively Silencing Nociceptor Sensory Neurons

Local anesthetics decrease the excitability of all neurons by blocking voltage-gated sodium channels non-selectively. We have developed a technology to silence only those sensory neurons – the nociceptors – that trigger pain, itch, and cough. I will tell you why and how we devised the strategy, the way we showed that it works, and will also discuss its implications for treating multiple human disorders.

From aura to neuroinflammation: Has imaging resolved the puzzle of migraine pathophysiology?

In this talk I will present data from imaging studies that we have been conducting for the past 20 years trying to shed light on migraine physiopathology, from anatomical and functional MRI to positron emission tomography.

Selectively Silencing Nociceptor Sensory Neurons

Local anesthetics decrease the excitability of all neurons by blocking voltage-gated sodium channels non-selectively. We have developed a technology to silence only those sensory neurons – the nociceptors – that trigger pain, itch, and cough. I will tell you why and how we devised the strategy, the way we showed that it works, and will also discuss its implications for treating multiple human disorders.

Migraine Headache: the revolution and its evolution

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.

Neuro-Immune Coupling: How the Immune System Sculpts Brain Circuitry

In this lecture, Dr Stevens will discuss recent work that implicates brain immune cells, called microglia, in sculpting of synaptic connections during development and their relevance to autism, schizophrenia and other brain disorders. Her recent work revealed a key role for microglia and a group of immune related molecules called complement in normal developmental synaptic pruning, a normal process required to establish precise brain wiring. Emerging evidence suggests aberrant regulation of this pruning pathway may contribute to synaptic and cognitive dysfunction in a host of brain disorders, including schizophrenia. Recent research has revealed that a person’s risk of schizophrenia is increased if they inherit specific variants in complement C4, gene plays a well-known role in the immune system but also helps sculpt developing synapses in the mouse visual system (Sekar et al., 2016). Together these findings may help explain known features of schizophrenia, including reduced numbers of synapses in key cortical regions and an adolescent age of onset that corresponds with developmentally timed waves of synaptic pruning in these regions. Stevens will discuss this and ongoing work to understand the mechanisms by which complement and microglia prune specific synapses in the brain. A deeper understanding of how these immune mechanisms mediate synaptic pruning may provide novel insight into how to protect synapses in autism and other brain disorders, including Alzheimer’s and Huntington’s Disease.

Neural mechanisms of navigation behavior

The regions of the insect brain devoted to spatial navigation are beautifully orderly, with a remarkably precise pattern of synaptic connections. Thus, we can learn much about the neural mechanisms of spatial navigation by targeting identifiable neurons in these networks for in vivo patch clamp recording and calcium imaging. Our lab has recently discovered that the "compass system" in the Drosophila brain is anchored to not only visual landmarks, but also the prevailing wind direction. Moreover, we found that the compass system can re-learn the relationship between these external sensory cues and internal self-motion cues, via rapid associative synaptic plasticity. Postsynaptic to compass neurons, we found neurons that conjunctively encode heading direction and body-centric translational velocity. We then showed how this representation of travel velocity is transformed from body- to world-centric coordinates at the subsequent layer of the network, two synapses downstream from compass neurons. By integrating this world-centric vector-velocity representation over time, it should be possible for the brain to form a stored representation of the body's path through the environment.

Targeting sleep oscillations to improve memory in schizophrenia

Feed-forward inhibition in Dentate Gyrus-CA3 instructs time-dependent re-organization of memory ensembles in prefrontal cortex

Sleep and the gut

Sleep is generally associated with the brain but poor sleep impacts the entire body - many diseases are caused or exacerbated by sleep loss. Our work is uncovering ways in which sleep and the body interact. We found a special, two-way relationship between sleep and the gut: the gut is uniquely impacted by sleep loss, and it actively controls sleep quality. These findings could help us understand the origins of sleep as well as develop strategies to offset the negative consequences of inadequate sleep.

Mixed representations in a visual-parietal-retrosplenial network for flexible navigation decisions

Sonic hedgehog signaling: from neurons to astrocytes during cortical circuit assembly

How do we find what we are looking for? The Guided Search 6.0 model

The talk will give a tour of Guided Search 6.0 (GS6), the latest evolution of Guided Search. Part 1 describes The Mechanics of Search. Because we cannot recognize more than a few items at a time, selective attention is used to prioritize items for processing. Selective attention to an item allows its features to be bound together into a representation that can be matched to a target template in memory or rejected as a distractor. The binding and recognition of an attended object is modeled as a diffusion process taking > 150 msec/item. Since selection occurs more frequently than that, it follows that multiple items are undergoing recognition at the same time, though asynchronously, making GS6 a hybrid serial and parallel model. If a target is not found, search terminates when an accumulating quitting signal reaches a threshold. Part 2 elaborates on the five sources of Guidance that are combined into a spatial “priority map” to guide the deployment of attention (hence “guided search”). These are (1) top-down and (2) bottom-up feature guidance, (3) prior history (e.g. priming), (4) reward, and (5) scene syntax and semantics. In GS6, the priority map is a dynamic attentional landscape that evolves over the course of search. In part, this is because the visual field is inhomogeneous. Part 3: That inhomogeneity imposes spatial constraints on search that described by three types of “functional visual field” (FVFs): (1) a resolution FVF, (2) an FVF governing exploratory eye movements, and (3) an FVF governing covert deployments of attention. Finally, in Part 4, we will consider that the internal representation of the search target, the “search template” is really two templates: a guiding template and a target template. Put these pieces together and you have GS6.

Human neuronal activity-dependent gene regulation in development and disease

Towards Operational and Falsifiable Definitions to Stimulate the Dialogue in the Neurophilosophy of Free Will

Corticothalamic cells: a critical link in forebrain sensorimotor loops

The Power and Limits of Neuroscience Research Paradigms on Action and Free Will

Microglia function and dysfunction in Alzheimer’s disease

Emerging genetic studies of late-onset Alzheimer’s Disease implicate the brain’s resident macrophages in the pathogenesis of AD. More than half the risk genes associated with late-onset AD are selectively expressed in microglia and peripheral myeloid cells; yet we know little about the underlying biology or how myeloid cells contribute to AD pathogenesis. Using single-cell RNA sequencing and spatial transcriptomics we identified molecular signatures that can be used to localize and monitor distinct microglia functional states in the human and mouse brain. Our results show that microglia assume diverse functional states in development, aging and injury, including populations corresponding to known microglial functions including proliferation, migration, inflammation, and synaptic phagocytosis. We identified several innate immune pathways by which microglia recognize and prune synapses during development and in models of Alzheimer’s disease, including the classical complement cascade. Illuminating the mechanisms by which developing synaptic circuits are sculpted is providing important insight on understanding how to protect synapses in Alzheimer’s and other neurodegenerative diseases of synaptic dysfunction.

Neuro-immune interactions in pain and host defense

The Chiu laboratory focuses on neuro-immune interactions in pain, itch, and tissue inflammation. Dr. Chiu’s research has uncovered molecular interactions between the nervous system, the immune system and microbes that modulates host defense. He has found that sensory neurons can directly detect bacterial pathogens and their toxins to produce pain. Neurons in turn release neuropeptides that modulate immune cells in host defense. These interactions occur at major tissue barriers in the body including the gut, skin and lungs. In this talk, he will discuss these major neuro-immune interactions and how understanding them could lead to novel approaches to treat pain or inflammation.

Sensing Light for Sight and Physiological Control

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.

Vagal sensory neurons that guard the airways

The vagus nerve contains a diversity of sensory neurons that detect peripheral stimuli such as blood pressure changes at the aortic arch, lung expansion during breathing, meal-induced stomach distension, and chemotherapeutics that induce nausea. Underlying vagal sensory mechanisms are largely unresolved at a molecular level, presenting tremendously important problems in sensory biology. We charted vagal sensory neurons by single cell RNA sequencing, identifying novel cell surface receptors and classifying a staggering diversity of sensory neuron types. We then generated a collection of ires-Cre knock-in mice to target each neuron type, and adapted genetic tools for Cre-based anatomical mapping, in vivo imaging, targeted ablation, and optogenetic control of vagal neuron activity. We found different sensory neuron types that innervate the lung and exert powerful effects on breathing, others that monitor and control the digestive system, and yet others that innervate that innervate the larynx and protect the airways. Together with Ardem Patapoutian, we also identified a critical role for Piezo mechanoreceptors in the sensation of airway stretch, which underlies a classical respiratory reflex termed the Hering-Breuer inspiratory reflex, as well as in the neuronal sensation of blood pressure and the baroreceptor reflex.

Cell Fate Determination in the Retina

The Cepko lab investigates the mechanisms that direct development of the central nervous system (CNS) of vertebrates, with a focus on the retina. These studies have revealed that the retina has distinct types of progenitor cells that are biased, or committed, to produce distinct types of daughter cells in terminal divisions. The gene regulatory networks that underlie these cell fate choices are being studied by analysis of both gene function and cis-regulatory networks. New methods that enable these studies have been developed, including high throughput enhancer assays and quantitative, inexpensive and sensitive multiplex in situ hybridization methods.