Champalimaud Colloquia

Historically, research on the brain has been working its way in from the outside world, hoping that such systematic exploration will take us some day to the middle and on through the middle to the output. Ever since the time of Aristotle, philosophers and scientists have assumed that the brain (or, more precisely, the mind) is initially a blank slate filled up gradually with experience in an outside-in manner. An alternative, brain-centric view, the one I am promoting, is that self-organized brain networks induce a vast repertoire of preformed neuronal patterns. While interacting with the world, some of these initially ‘nonsensical’ patterns acquire behavioral significance or meaning. Thus, experience is primarily a process of matching preexisting neuronal dynamics to events in the world. I suggest that perpetually active, internal dynamic is the source of cognition, a neuronal operation disengaged from immediate senses.

The gut microbiota is emerging as an important modulator of brain function and behavior, as several recent discoveries reveal substantial effects of the microbiome on neurophysiology, neuroimmunity and animal behavior. Despite these findings supporting a “microbiome-gut-brain axis”, the molecular and cellular mechanisms that underlie interactions between the gut microbiota and brain remain poorly understood. To uncover these, the Hsiao laboratory is mining the human microbiota for microbial modulators of host neuroactive molecules, investigating the impact of microbiota-immune system interactions on neurodevelopment and examining the microbiome as an interface between gene-environment interactions in neurological diseases. In particular, our research on effects of the maternal microbiome on offspring development in utero are revealing novel interactions between microbiome-dependent metabolites and fetal thalamocortical axonogenesis. Overall, we aim to dissect biological pathways for communication between the gut microbiota and nervous system, toward understanding fundamental interactions between physiological systems that impact brain and behavior.

According to Hamilton’s inclusive fitness hypothesis, kinship is an organizing principle of social behavior. Behavioral evidence supporting this hypothesis includes the ability to recognize kin and the adjustment of behavior based on kin preference with respect to altruism, attachment and care for offspring in insect societies. Despite the fundamental importance of kinship behavior, the underlying neural mechanisms are poorly understood. We repeated behavioral experiments by Hepper on behavioral preference of rats for their kin. Consistent with Hepper’s work, we find a developmental time course for kinship behavior, where rats prefer sibling interactions at young ages and express non-sibling preferences at older ages. In probing the brain areas responsible for this behavior, we find that aspiration lesions of the lateral septum but not control lesions of cingulate cortices eliminate the behavioral preference in young animals for their siblings and in older rats for non-siblings. We then presented awake and anaesthetized rats with odors and calls of age- and status-matched kin (siblings and mothers) and non-kin (non-siblings and non-mothers) conspecifics, while performing in vivo juxta-cellular and whole-cell patch-clamp recordings in the lateral septum. We find multisensory (olfactory and auditory) neuronal responses, whereby neurons typically responded preferentially but not exclusively to individual social stimuli. Non-kin-odor responsive neurons were found dorsally, while kin-odor responsive neurons were located in ventrally in the lateral septum. To our knowledge such an ordered representation of response preferences according to kinship has not been previously observed and we refer this organization as nepotopy. Nepotopy could be instrumental in reading out kinship from preferential but not exclusive responses and in the generation of differential behavior according to kinship. Thus, our results are consistent with a role of the lateral septum in organizing mammalian kinship behavior.

This open colloquia session is part of the special workshop entitled "Obesity at the Interface of Neuroscience and Physiology II". Abstract: Proopiomelanocortin (POMC)- and agouti related peptide (AgRP)-expressing neurons in the arcuate nucleus of the hypothalamus (ARH) are critical regulators of food intake and energy homeostasis. They rapidly integrate the energy state of the organism through sensing fuel availability via hormones, nutrient components and even rapidly upon sensory food perception. Importantly, they not only regulate feeding responses, but numerous autonomic responses including glucose and lipid metabolism, inflammation and blood pressure. More recently, we could demonstrate that sensory food cue-dependent regulation of POMC neurons primes the hepatic endoplasmic reticulum (ER) stress response to prime liver metabolism for the postpramndial state. The presentation will focus on the regulation of these neurons in control of integrative physiology, the identification of distinct neuronal circuitries targeted by these cells and finally on the broad range implications resulting from dysregulation of these circuits as a consequence of altered maternal metabolism.

Over the last several decades, the tractable response properties of parahippocampal neurons have provided a new access key to understanding the cognitive process of self-localization: the ability to know where you are currently located in space. Defined by functionally discrete response properties, neurons in the medial entorhinal cortex and hippocampus are proposed to provide the basis for an internal neural map of space, which enables animals to perform path-integration based spatial navigation and supports the formation of spatial memories. My lab focuses on understanding the mechanisms that generate this neural map of space and how this map is used to support behavior. In this talk, I’ll discuss how learning and experience shapes our internal neural maps of space to guide behavior.

Humans spend a lifetime learning, storing and refining a repertoire of motor memories. However, it is unknown what principle underlies the way our continuous stream of sensori-motor experience is segmented into separate memories and how we adapt and use this growing repertoire. Here we develop a principled theory of motor learning based on the key insight that memory creation, updating, and expression are all controlled by a single computation – contextual inference. Unlike dominant theories of single-context learning, our repertoire-learning model accounts for key features of motor learning that had no unified explanation and predicts novel phenomena, which we confirm experimentally. These results suggest that contextual inference is the key principle underlying how a diverse set of experiences is reflected in motor behavior.

Behavior varies even among genetically identical animals raised in the same environment. However, little is known about the circuit or anatomical underpinnings of this individuality, though previous work implicates sensory periphery. Drosophila olfaction presents an ideal model to study the biological basis of behavioral individuality, because while the neural circuit underlying olfactory behavior is well-described and highly stereotyped, persistent idiosyncrasy in behavior, neural coding, and neural wiring have also been described. Projection neurons (PNs), which relay odor signals sensed by olfactory receptor neurons (ORNs) to deeper brain structures, exhibit variable calcium responses to identical odor stimuli across individuals, but how these idiosyncrasies relate to individual behavioral responses remains unknown. Here, using paired behavior and two-photon imaging measurements, we show that idiosyncratic calcium dynamics in both ORNs and PNs predict individual preferences for an aversive monomolecular odorant versus air, suggesting that variation at the periphery of the olfactory system determines individual preference for an odor’s presence. In contrast, PN, but not ORN, calcium responses predict individual preferences in a two-odor choice assay. Furthermore, paired behavior and immunohistochemistry measurements reveal that variation in ORN presynaptic density also predicts two-odor preference, suggesting this site is a locus of individuality where microscale circuit variation gives rise to idiosyncrasy in behavior. Our results demonstrate how a neural circuit may vary functionally and structurally to produce variable behavior among individuals.

Social interactions are central to the human experience, yet it is also one of the faculty of the brain that is the most impaired by mental illness. Similarly, social interactions are essential for animals to survive, reproduce, and raise their young. Over the years, my lab has attempted to decipher the unique characteristics of social recognition: what are the unique cues that trigger distinct social behaviors, what is the nature and identity of social behavior circuits, how is the function of these circuits different in males and females and how are they modulated by the animal physiological status? In this lecture, I will describe our recent progress in using genetic, imaging, molecular and behavioral approaches to understand how the brain controls specific social behaviors in both males and females, and how areas throughout the brain participate in the positive and negative controls of specific social interactions. I will also describe how new approaches of single cell transcriptomics have enabled us to uncover specific cell populations involved in distinct social behaviors and the basis of their activity modulation according to the animal state.

Neural and behavioral responses to sensory stimuli are notoriously variable from trial to trial. Does this mean the brain is inherently noisy or that we don’t completely understand the nature of the brain and behavior? Here we monitor the state of activity of the animal through videography of the face, including pupil and whisker movements, as well as walking, while also monitoring the ability of the animal to perform a difficult auditory or visual task. We find that the state of the animal is continuously changing and is never stable. The animal is constantly becoming more or less activated (aroused) on a second and subsecond scale. These changes in state are reflected in all of the neural systems we have measured, including cortical, thalamic, and neuromodulatory activity. Rapid changes in cortical activity are highly correlated with changes in neural responses to sensory stimuli and the ability of the animal to perform auditory or visual detection tasks. On the intracellular level, these changes in forebrain activity are associated with large changes in neuronal membrane potential and the nature of network activity (e.g. from slow rhythm generation to sustained activation and depolarization). Monitoring cholinergic and noradrenergic axonal activity reveals widespread correlations across the cortex. However, we suggest that a significant component of these rapid state changes arise from glutamatergic pathways (e.g. corticocortical or thalamocortical), owing to their rapidity. Understanding the neural mechanisms of state-dependent variations in brain and behavior promises to significantly “denoise” our understanding of the brain.

Today, considerable information is available on the organization and operation of the neural networks that generate the motor output for animal locomotion, such as swimming, walking, or flying. In recent years, the question of which neural mechanisms are responsible for task-specific and flexible adaptations of locomotor patterns has gained increased attention in the field of motor control. I will report on advances we made with respect to this topic for walking in insects, i.e. the leg muscle control system of phasmids and fruit flies. I will present insights into the neural basis of speed control, heading, walking direction, and the role of ground contact in insect walking, both for local control and intersegmental coordination. For these changes in motor activity modifications in the processing of sensory feedback signals play a pivotal role, for instance for movement and load signals in heading and curve walking or for movement signals that contribute to intersegmental coordination. Our recent findings prompt future investigations that aim to elucidate the mechanisms by which descending and intersegmental signals interact with local networks in the generation of motor flexibility during walking in animals.

In the olfactory system, cholinergic modulation has been associated with contrast modulation and changes in receptive fields in the olfactory bulb, as well the learning of odor associations in the olfactory cortex. Computational modeling and behavioral studies suggest that cholinergic modulation could improve sensory processing and learning while preventing pro-active interference when task demands are high. However, how sensory inputs and/or learning regulate incoming modulation has not yet been elucidated. We here use a computational model of the olfactory bulb, piriform cortex (PC) and horizontal limb of the diagonal band of Broca (HDB) to explore how olfactory learning could regulate cholinergic inputs to the system in a closed feedback loop. In our model, the novelty of an odor is reflected in firing rates and sparseness of cortical neurons in response to that odor and these firing rates can directly regulate learning in the system by modifying cholinergic inputs to the system.

Maintaining posture is a vital challenge for all freely-moving organisms. As animals grow, their relationship to destabilizing physical forces changes. How does the nervous system deal with this ongoing challenge? Vertebrates use highly conserved vestibular reflexes to stabilize the body. We established the larval zebrafish as a new model system to understand the development of the vestibular reflexes responsible for balance. In this talk, I will begin with the biophysical challenges facing baby fish as they learn to swim. I’ll briefly review published work by David Ehrlich, Ph.D., establishing a fundamental relationship between postural stability and locomotion. The bulk of the talk will highlight unpublished work by Kyla Hamling. She discovered that a small (~50) population of molecularly-defined brainstem neurons called vestibulo-spinal cells act as a nexus for postural development. Her loss-of-function experiments show that these neurons contribute more to postural stability as animals grow older. I’ll end with brief highlights from her ongoing work examining tilt-evoked responses of these neurons using 2-photon imaging and the consequences of downstream activity in the spinal cord using single-objective light-sheet (SCAPE) microscopy