WTI Symposium: Building Blocks of Behavior

Refreshments will be available beginning at at 8:30 AM, and doors will open at 8:45 AM.

Aggregates of stem cells can break symmetry and self-organize the morphogenesis of embryo-like structures and gene expression patterns (e.g., organoids and embryoids). How multicellular self-organization emerges from signaling interactions between stem cells is not well understood. Tools from synthetic biology for measuring, recording, and controlling cell signaling dynamics enable quantitative tests of physical theories of symmetry breaking and pattern formation. We describe how this approach to ‘synthetic developmental biology’ can be used to decode and control programs of multicellular self-organization. We focus on describing symmetry breaking in the gastruloid, a stem cell model which recapitulates aspects of anteroposterior (A-P) patterning. It has been proposed that a reaction-diffusion Turing instability in Wnt signaling defines the posterior of the gastruloid. However, distinguishing candidate mechanisms of polarization requires linking early cell states to future cell positions along the A-P axis. We use synthetic “signal-recording” gene circuits to study symmetry breaking in the gastruloid during the evolution of a polarized Wnt pattern from an initially homogeneous state. We find that cell sorting, rather than a long-range Turing mechanism, rearranges early domains of Wnt activity into a single pole which defines the gastruloid axis. We also trace the emergence of Wnt domains to earlier heterogeneity in Nodal activity, even before Wnt activity is detectable. Our results define a mechanism through which aggregates of stem cells can form a patterning axis even in the absence of external spatial cues. We also discuss ongoing work towards guiding morphogenic signals with light, as well as the use of all-optical electrophysiology (i.e., paired optogenetic stimulation and voltage imaging) to investigate electrical reaction-diffusion patterning in engineered epithelial tissues. Finally, we discuss future opportunities to apply these methods to investigate genetic and electrophysiological pattern formation in neural organoids.

Whether deciding to pursue a mate or attack a competitor, social interactions are critical for survival. Aggressive behaviors are governed by social decision-making that must continuously assess the risk of injury and potential reward to guide approach, engagement, continuation, and disengagement. However, little is known about the neuronal circuit mechanisms underlying these complex aspects of aggression.

The fruit fly, Drosophila melanogaster, constitutes a powerful model for the mechanistic dissection of such cognitive processes due to its genetic accessibility, complete brain-wide connectome, and sophisticated behaviors. Recently, we uncovered a cell type underlying persistent female aggression (Schretter et al., 2020; Chiu,…,Schretter, 2023). Through mapping this complete female aggression circuit, we found these neurons exert a large part of their behavioral effects through gating visual processing (Schretter et al., paper one, in preparation). Interestingly, male courtship pursuit uses many of the same circuit motifs suggesting common mechanisms for continuing social behaviors (Schretter et al., paper one, in preparation). As persistent aggression risks injury or death, mechanisms for conversely shutting down or disengaging are equally critical for survival. Further circuit and quantitative behavioral analysis uncovered a novel neuronal subset downregulating aggression in females and males (Schretter et al., paper two, in preparation). Identification of these sex-specific and shared mechanisms reveals general principles for circuits controlling social behaviors and lays the foundation for a mechanistic understanding of flexible social decision-making.

We will take a short break between speakers.

Oxytocin is a neuropeptide critical for maternal physiology and social behavior and is thought to be dysregulated in several neuropsychiatric disorders. Despite the biological and neurocognitive importance of oxytocin signaling, methods are lacking to activate oxytocin receptors with high spatiotemporal precision in the brain and periphery in mammalian tissues. Here we developed and validated caged analogs of oxytocin which are functionally inert until cage release is triggered by ultraviolet light. We examined how focal versus global oxytocin application affected calcium wave propagation in mouse mammary tissue and to control uterine contractions with light. We validated the application of caged oxytocin in the hippocampus and auditory cortex with electrophysiological recordings in vitro and demonstrated that oxytocin uncaging can accelerate onset of mouse maternal behavior in vivo. Together, these results demonstrate that optopharmacological control of caged peptides is a robust tool for modulating neuropeptide signaling throughout the brain and body.

Lunch will be provided for those who registered by January 12.

Neural control of cardiac function is essential for survival, yet the functional diversity of the sensory and motor circuits of the heart remains poorly understood. Here we take a multidisciplinary approach, combining systems neuroscience techniques, genetics, and control theory to study the role of cardiac sensory and motor circuits in larval zebrafish. While larval zebrafish’s optic and genetic accessibility has made it a widely used organism for studying how the brain processes environmental cues to modulate behavior, it had not yet been used to study organ control or the autonomic nervous system (ANS) from a systems neuroscience perspective. Thus, we use calcium imaging, optogenetics, pharmacology, and electron microscopy to map the developmental time course of anatomical and functional innervation of the heart. We identify the emergence of parasympathetic and sympathetic control of the heart, as well as the anatomically defined neural populations needed for heart modulation. We also show the onset of cardiac sensing and identify a new type of interoceptor. Our study provides a timeline of developmental landmarks of the autonomic circuits for heart feedback control and sets the stage for future mechanistic studies of neurocardiac circuits.

Animals exhibit an extraordinary capability to adapt and learn, allowing for the seamless navigation of new environments or the acquisition of new behaviors to accomplish a task. To support this behavioral flexibility, many of the underlying neural circuits possess an equivalent malleability, dynamically changing their activity or function to optimize task performance. In this talk, I will first present work that examines this concept in the rodent navigation system and identifies novel ways in which entorhinal representations of external space change with the spatial task. Second, I will present work that examines this concept in the motor system, specifically focusing on how neural circuits in the basal ganglia flexibly change their function and activity to support the learning of complex motor skills. Last, I will conclude with my plans to study the algorithmic principles driving rapid learning, with a focus on how knowledge accumulated across multiple tasks can speed up learning on a single task.

The symposium will conclude at 4:00 PM.