2022-23 Neuroscience Seminar Series

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Debra Bangasser, PhD

Temple University

Department of Psychology

Early resource scarcity causes lasting changes in motivated behavior

Monday, August 22, 2022 3:00 PM Central Hosted by Jamie Palmer, INS

Bangasser Lab ↗

Abstract

Early life trauma is a risk factor for disorders characterized by altered motivation, including substance use disorder and depression. However, early adversity that is not overwhelming can promote later resilience to stress-related disorders. Our laboratory models brief early life scarcity using the Limited Bedding and Nesting (LBN) manipulation, in which rat dams and pups are reared in a low resource environment from pups PND 2-9 and compared to control rats raised in standard housing conditions. This talk will detail how LBN causes sex- and reinforcer-specific effects on motivated behavior. In male rats, prior exposure to LBN reduces self-administration and motivation for a drug reward (morphine), while increasing motivation for the natural rewards of sucrose and a social partner. In contrast, in female rats, LBN exposure impairs motivation for sucrose, consistent with an anhedonia-like phenotype. Yet, LBN does not disrupt motivation for social reward or morphine in females, perhaps because these rewards are so reinforcing a deficit is not detectable. To identify factors that mediate the effects of LBN on behavior, we are delineating molecular changes in the nucleus accumbens (NAc), a region that is a hub in reward circuitry. RNA sequencing revealed that LBN produced sex-specific changes in NAc gene transcription, including in genes related to glutamate transmission. Using a genome-wide histone posttranslational modification (PTM) screen, we identified sex-specific histone marks altered by LBN and are linking PTMs to transcriptional changes. Importantly, identifying factors that promote vulnerability/resilience to certain reinforcers may lead to novel treatment options for disorders characterized by altered motivated behavior.

Avishek Adhikari, PhD

University of California, Los Angeles

Department of Psychology

Control of feeding by a bottom-up brainstem-subthalamic pathway

Monday, August 29, 2022 3:00 PM Central Hosted by Dr. Lief Fenno

Adhikari Lab ↗

Abstract

Investigative exploration and foraging leading to food consumption have vital importance, but are not well-understood. Since GABAergic inputs to the lateral and ventrolateral periaqueductal gray (l/vlPAG) control such behaviors, we dissected the role of vgat-expressing GABAergic l/vlPAG cells in exploration, foraging and hunting. Here, we show that vgat l/vlPAG cells encode approach to food and consumption of both live prey and non-prey foods. The activity of these cells is necessary and sufficient for inducing consumption, and vgat l/vlPAG activation produces exploratory foraging and compulsive eating without altering defensive behaviors. Moreover, l/vlPAG vgat cells are bidirectionally interconnected to several feeding, exploration and investigation nodes, including the zona incerta. Remarkably, the vgat l/vlPAG projection to the zona incerta bidirectionally controls approach towards food leading to consumption. These data indicate the PAG is not only a final downstream target of top-down exploration and foraging-related inputs, but that it also influences these behaviors through a bottom-up pathway.

Omar Ahmed, PhD

University of Michigan

Department of Psychology

Spatial Orientation & Head Velocity Circuits in the Retrosplenial Cortex

Monday, September 19, 2022 3:00 PM Central Hosted by Dr. MacKenzie Howard

Ahmed Lab ↗

Abstract

Successful spatial navigation and orientation are critical for mammalian survival. Lesions to a brain region called the retrosplenial cortex (RSC) dramatically impair spatial orientation abilities, emphasizing the need to decipher the unique aspects of RSC circuit computations supporting its GPS-like functions. Here, using optogenetic circuit mapping, transcriptomics, in vivo recordings, and computational modeling we build towards a comprehensive cellular and circuit understanding of the RSC. We identify a uniquely small and excitable pyramidal neuron and show that it is the primary recipient of spatially-relevant inputs to the RSC. Observed synaptic dynamics enable these small neurons to compute the speed of head rotation, despite receiving head direction inputs that do not explicitly encode speed. We also show that two distinct fast brain rhythms identified in the RSC are the signatures of two very different long-range neuronal synchronization mechanisms, each precisely controlled by the speed of movement. These findings are confirmed across both rats and mice, highlighting key evolutionarily conserved circuit computations performed by the RSC in support of successful spatial navigation.

Denise Cai, PhD

Icahn School of Medicine at Mount Sinai

Department of Neuroscience

The brain in motion - How ensemble fluidity supports memory updating.

Monday, October 3, 2022 3:00 PM Central Hosted by Ayesha Nadiadwala, INS

Cai Lab ↗

Abstract

Creating stable memories is critical for survival. An animal relies on past learning to navigate its environment, avoid dangerous situations, and find needed resources. Because the environment is dynamic, stable memories must be updated with new information to enable responses to changing threats (a specific danger) and rewards (such as food and water). The brain circuits involved in memory and learning require both stability and flexibility. Using in vivo calcium imaging, immediate-early gene tagging, and chemogenetics, we demonstrate how the dynamic activity of neural ensembles supports the “tug of war” between memory stability and flexibility in a mouse model.

Attila Losonczy, MD, PhD

Columbia University

Zuckerman Mind Brain Behavior Institute

Assembly and functional organization of neural circuits for episodic memory

Monday, October 10, 2022 3:00 PM Central Hosted by Dr. Laura Colgin

Losonczy Lab ↗

Abstract

Understanding neural mechanisms of associative learning supporting adaptive behaviors in the mammalian brain is a longstanding challenge in neuroscience. In humans, our expanded capacity for episodic learning and memory defines our conscious experience, and memory deficits are among the most devastating symptoms of neurodegenerative and neuropsychiatric disorders. Despite these, experimental progress has at a best-been pedestrian in uncovering fundamental principles of learning and memory, and there is yet little consensus concerning bona fide neural substrates of episodic memory and how they operate at a mechanistic level. My research is aimed at addressing these unmet challenges in the mammalian hippocampus by using a novel conceptual framework and cutting-edge methodologies. In my talk, I will present an overview of my recent contributions to memory research at multiple levels. First, I will review the tight links my work has identified between cellular diversity of hippocampal circuits and memory-related behaviors. Second, I will discuss our recent results on how local circuit connectivity and plasticity govern memory-coding ensemble formation. Finally, I introduce subcellular organizational principles of memory formation and storage that our studies have identified, revealing compartmentalized and dynamic interactions between synaptic/molecular and dendritic processes. These lines of research are centered at the catalytic intersection of synaptic, cellular/molecular, and circuit/systems neuroscience and support a novel conceptual framework for memory operations: developmental programs and genetic specification at the level of small networks of neurons (‘microcircuits’), together with experience-dependent plasticity mechanisms, provide memory circuits with the computational capacity and flexibility to implement diverse memory functions.

Mrinalini Hoon, PhD

University of Wisconsin

Department of Ophthalmology and Visual Sciences

Molecules and mechanisms driving assembly of retinal circuits

Monday, October 17, 2022 3:00 PM Central Hosted by Dr. Amy Lee

Hoon Lab ↗

Abstract

The retina has specialized circuits for processing visual information. These circuits utilize specialized connectivity (synaptic) motifs for efficient signal transfer. One of these motifs that is heavily employed by retinal glutamatergic second order neurons is ‘presynaptic inhibition’ which is mediated by inhibitory synapses across the axon terminals of these neurons. Presynaptic inhibition critically regulates the transfer of signals from these terminals to downstream retinal output neurons. By combining murine transgenic tools with single cell electrophysiology, high resolution light and electron microscopy we are studying the mechanisms that regulate the formation and function of synapses that mediate presynaptic inhibition in the dim-light (night vision) retinal pathway. We find a role for an early GABA receptor type in the establishment and function of these synapses as well as a novel role for the postsynaptic adhesion protein LRRTM4. In addition to molecular mechanisms, the maturation of these synapses is also regulated by visually driven activity. Thus, a coordination of molecular and activity-dependent mechanisms shapes the assembly and function of these retinal microcircuits.

Shai Silberberg, PhD

National Institute of Neurological Disorders and Stroke

Director of Research Quality

Assuring a bright future for biomedical research

Monday, October 31, 2022 3:00 PM Central Hosted by Dr. Amy Lee

Silberberg NIH Profile ↗

Abstract

The presentation will focus on the current state of rigor and transparency in biomedical research, the root causes for the current state, what actions have been taken by NIH and other stakeholders to improve rigor and transparency, and what remains to be done.

Mark Harnett, PhD

Massachusetts Institute of Technology

McGovern Institute for Brain Research

Biophysics for Cortical Computation

Monday, January 9, 2023 3:00 PM Central Hosted by Dr. Nace Golding

Harnett Lab ↗

Abstract

The biological substrates of computation in the cortex remain elusive. While the remarkable recent progress of artificial neural systems has generated important insights into cortical function, these networks employ highly simplified model neurons. Real cortical neurons receive thousands of diverse synaptic inputs distributed across extensive dendritic arbors that exhibit highly nonlinear properties, providing opportunities for complex subcellular computation. This could provide neural networks with increased power, flexibility, and/or efficiency. However, the contributions of these kinds of biological mechanisms to the cortical computations that underlie behavior remain unclear. In this talk, I will present my lab’s recent progress in evaluating the biophysical substrates, engagement, and utility of synaptic and dendritic mechanisms in the adult mammalian cortex. I will discuss a multidisciplinary synapses-to-systems analysis of the interactive circuit between the visual and retrosplenial cortices in mice, in which we aim to connect biophysical processes at the level of single neurons to circuit dynamics during computation. I will link this to our recent work on new forms of synaptic plasticity in the adult cortex. I will also discuss our efforts to understand how biophysical properties (ion channels and dendritic morphology) shape cortical neuronal input-output functions across the phylogenetic tree of mammals, from Etruscan shrews to humans. Our goals across these lines of inquiry are to understand general principles of cortical design and function, and to facilitate the development of new artificial neural networks with enhanced capabilities.

Saskia Haegens, PhD

Columbia University - Department of Psychiatry

Radboud University Nijmegen - Centre for Cognitive Neuroimagine

Oscillatory building blocks underlying perception & cognition

Monday, January 30, 2023 3:00 PM Central Hosted by Dr. Laura Colgin

Haegens Lab ↗

Abstract

In daily life our brains receive a continuous stream of sensory input. Effective processing in a complex natural environment requires the selection of relevant information and suppression of irrelevant input. I am interested in how brain rhythms help shape the internal state prior to perception, and thereby influence processing of external information, e.g. in the context of sensory detection, discrimination and decision-making. In my lab we use several complementary methods to study these neuronal dynamics from the micro- to the macro-level, including spike and LFP recordings, ECoG, and MEG.

Michael Bruchas, PhD

University of Washington

Center in Neurobiology of Addiction, Pain and Emotion

Decoding Heterogeneity of the Locus Coeruleus Noradrenergic System in Arousal and Stress

Monday, February 6, 2023 3:00 PM Central Hosted by Dr. Lauren Dobbs

Bruchas Lab ↗

Abstract

All animals must tune their psychological and physiological arousal levels to maintain homeostasis and respond to salient stimuli in the environment. In vertebrates, this is accomplished by tuning the activity of the locus coeruleus (LC), a structure in the brainstem that releases most of the norepinephrine across the neuraxis. Changes in LC firing patterns and the differential activity of LC ensembles are crucial for coordinating states of arousal across distant brain regions; however, how these features of LC activity are established remain largely unknown. In this manuscript, we identify and profile a diverse population of GABAergic neurons that surrounds the LC and responds to salient stimuli to modulate arousal-related behaviors. Many human neuropsychiatric diseases are characterized by dysregulation in the LC and cognitive arousal, including drug addiction, anxiety, and depression. These findings greatly improve our understanding of the regulation of arousal and related behavior in the brain and offer new potential therapeutic targets for these psychiatric diseases.

John Reynolds, PhD

The Salk Institute for Biological Studies

Systems Neurobiology Laboratory

Intrinsic traveling waves of neural activity in Area MT of the awake, behaving monkey regulate the gain of stimulus-evoked responses and perceptual sensitivity.

Monday, February 13, 2023 3:00 PM Central Hosted by Dr. Kristen Harris

Reynolds Lab ↗

Abstract

Perceptual sensitivity varies from moment to moment. One potential source of this variability is spontaneous fluctuations in neural sensitivity. Using newly developed techniques to characterize the moment-to-moment dynamics of noisy multi-electrode data, we find that spontaneous cortical activity is organized into traveling waves that traverse visual cortex several times per second. Recording in Area MT of the common marmoset, we find that these intrinsic traveling waves (iTWs) regulate both the gain of the stimulus-evoked spiking response and the monkey’s perceptual sensitivity. In monkeys trained to detect faint visual targets, the iTW state prior to target onset predicts the magnitude of target-evoked neural response and the likelihood that the monkey will detect the target. A large-scale spiking network model with conductance-based synapses recapitulates the properties of iTWs measured in vivo. The model shows that iTWs naturally emerge from the delays that occur as action potentials traverse unmyelinated horizontal fibers. The model predicts that iTWs are sparse, in the sense that only a small fraction of the neural population participates in any individual iTW. As a result, iTWs can occur without inducing correlated variability, which we have found, in separate experiments, can impair sensory discrimination. We thus refer to the model as the sparse-wave model of iTWs. The model also predicts that iTWs fall into feature-selective motifs whose selectivity stems from the horizontal fibers that preferentially connect similarly tuned feature domains. Consistent with this prediction, we find distinct clusters of iTW motifs. Some motifs modulate neural activity and perceptual sensitivity in a feature-selective manner. Taken together, these findings lead to the conclusion that traveling waves strongly modulate neural and perceptual sensitivity, in a feature-selective manner. These findings are consistent with studies of traveling waves in the motor system, suggesting that iTWs may represent a brain-wide computational principle.

Related Literature

Davis, W., Muller, L., Martinez-Trujillo, J., Sejnowski, T., Reynolds, J.H. Spontaneous travelling cortical waves gate perception in behaving primates (2020) Nature. DOI: https://www.nature.com/articles/ s41586-020-2802-y.

Davis, Z.W., Benigno, G.B., Fletterman, C., Desbordes, T., Steward, C., Sejnowski, T.J., Reynolds, J.H., Muller, L. Spontaneous traveling waves naturally emerge from horizontal fiber time delays and travel through locally asynchronous-irregular states. (2021) Nature Communications. 12(1):6057. DOI: 10.1038/s41467-021-26175-1.

Davis, Z.W., Muller, L., Reynolds, J. Spontaneous Spiking Is Governed By Broadband Fluctuations. (2022) Journal of Neuroscience. DOI: 10.1523/JNEUROSCI.1899-21.2022.

Ofer Yizhar, PhD

Weizmann Institute of Science, Israel

Department of Brain Sciences

Optogenetic dissection of local and long-range connections in prefrontal circuits

Thursday, March 2, 2023 10:00 AM Central Hosted by Dr. Lief Fenno

Yizhar Lab ↗

Abstract

The prefrontal cortex (PFC) plays an important role in regulating social functions in mammals, and impairments in this region have been linked with social dysfunction in psychiatric disorders. The PFC plays a part in multiple brain-wide networks regulating behavior, and its long-range connections to different cortical and subcortical targets are thought to be involved in distinct behavioral functions. How is information about the multitude of cognitive/behavioral processes routed into and out of the PFC circuit? We are interested in understanding how PFC microcircuits process behavioral information, and how distinct PFC output neuron populations regulate learning, decision-making and social behavior.

I will first describe a set of experiments aimed at understanding the structure of synaptic connectivity among amygdala-projecting neurons in the mPFC. Using single-neuron two-photon optogenetic stimulation and imaging, we demonstrated that these neurons show unique layer-specific connectivity features compared with randomly-sampled mPFC neurons. I will then descibe the engineering of new optogenetic tools for silencing of long-range axonal projections. To efficiently suppress synaptic transmission, we designed a new set of inhibitory bistable rhodopsins that couple to the G_i/osignaling pathway and can be used to suppress synaptic release in vitro and in vivo, in a spatially and temporally-precise manner. New tools within this family allow spectral multiplexing for combined imaging and optogenetic silencing, opening up new avenues for circuit interrogation work.

Brian Kraemer, PhD

University of Washington

Division of Gerontology & Geriatric Medicine

Leveraging Model Organism Genetics to Inform Neurotherapeutic Approaches in Alzheimer’s Disease and Related Disorders

Monday, March 6, 2023 3:00 PM Central Hosted by Dr. Jon Pierce

Kraemer Lab ↗

Abstract

Abnormal tau, amyloid beta, and TDP-43 proteins forms aggregates in disease-affected neurons in patients with Alzheimer’s Disease and related dementia. Mutations in the genes encoding these aggregating proteins can cause inherited dementia in families. By expressing human mutant tau, and TDP-43 protein in C. elegans neurons, we have modelled aspects of dementia pathobiology. This animal model exhibits severe motor dysfunction, progressive neurodegeneration, and accumulation of abnormally modified aggregated proteins. To identify genes regulating proteotoxicity C. elegans, we have surveyed all C. elegans genes to find several that participate in neurodegeneration. We have leveraged these findings to explore new molecular mechanisms contributing to neurodegeneration in the mammalian brain.

Andre Berndt, PhD

University of Washington

Department of Bioengineering

Enlighten neurophysiology with genetically encoded sensors

Monday, March 20, 2023 3:00 PM Central Hosted by Dr. Lief Fenno

Berndt Lab ↗

Abstract

Summary: Genetically encoded sensors, combined with fluorescent microscopy, have revolutionized real-time monitoring of dynamic physiological processes. However, the number of high-performing sensors that meet experimental needs is still limited, while there are hundreds of biological compounds for which no sensors exist. The Berndt lab develops sensors by integrating state-of-the-art approaches such as high-throughput screening, machine learning, and predictive protein engineering. These combined efforts aim to address the intrinsic complexity of protein sensors which effectively hinders the fast deployment of new tools. We engineered novel sensors for reactive oxygen species, calcium, dopamine, and opioids. One highlight is calcium indicators, predicted by machine learning ensemble models, with increased dynamic range without sacrificing calcium sensitivity and fast kinetics.

Furthermore, we focus on optimizing multiplexed approaches, such as combining the readout of ROS and calcium from the same cells. Monitoring these processes could reveal critical insights into the pathophysiology of cardiovascular and neurodegenerative diseases and neuromodulation in motivated behaviors. Our sensors have been optimized and validated in various host systems such as mammalian cell cultures, IPSC-derived neurons and cardiomyocytes, brain slices, and behaving animals. Our future efforts aim to build custom-designed tools that meet cardiovascular and neuroscience research requirements, such as high ligand selectivity, affinity, large response amplitudes, low toxicity, fast kinetics, and cell-type and cell-type and subcellular targeting.

Sung-Yon Kim, PhD

Seoul National University

Institute of Molecular Biology and Genetics

Warm and full: neural circuits for behavioral regulation of homeostasis

Monday, March 27, 2023 3:00 PM Central Hosted by Drs. Lief Fenno and Bob Messing

Kim Lab ↗

Abstract

Many of our behaviors are intrinsically motivated by a need to maintain homeostasis, including that of body temperature, energy, and fluid levels. Despite their importance, numerous seemingly simple questions remain unresolved in this field. My presentation will focus on our ongoing efforts to address two of these issues in mouse models. The first part attempts to address: How do we turn on the heat when it is cold? Thermoregulatory behavior is among the least-studied classic motivated behaviors—until recently, no forebrain region or cell type was shown to be necessary for these responses. We recently identified the lateral hypothalamus (LH) and its Vgat+ neurons as a necessary region and cell type (Jung et al., Neuron 2022). LH Vgat+ neurons encode thermoregulatory behavior, as well as the reward value of thermal stimuli, and parabrachial inputs are required for both this encoding and thermoregulatory behavior. Notably, two-photon Ca2+ imaging revealed distinct LH Vgat+ subpopulations encoding thermal and caloric rewards. The functional heterogeneity within the LH Vgat+ population will be discussed in detail. The second part tries to answer: How do we stop eating when we are “mechanically” full? Mechanosensory feedback from the digestive tract to the brain is critical for limiting excessive food and water intake, but the underlying gut-brain communication pathways and mechanisms remain poorly understood. We found that Pdyn+ neurons in the parabrachial nucleus monitor the intake of both fluids and solids, using mechanosensory signals arising from the upper digestive tract (Kim et al., Nature 2020; also see Kim et al., Nat Rev Neurosci 2022). Upon receipt of the mechanosensory signals, these neurons produce aversive and sustained appetite-suppressing signals that serve as negative feedback on ingestion to prevent harmful overconsumption. Our continuing efforts to pinpoint the precise site of the origin of mechanosensory feedback signals and the downstream circuit that integrates these signals with appetite-promoting signals will also be described. In sum, our findings lay the groundwork for future research into the neural bases of behavioral thermoregulation and mechanosensory feedback control of ingestion, as well as their relationships with other motivated behaviors.

Edwin Chapman, PhD

University of Wisconsin and HHMI

Special Joint Seminar with the College of Pharmacy

New insights into synaptic vesicle biogenesis, dynamics, and modes of release

Thursday, March 30, 2023 10:00 AM Central Hosted by Dr. Somshuvra Mukhopadhyay

Chapman Lab ↗

Abstract

Pending.

Elizabeth Heller, PhD

University of Pennsylvania

Department of Pharmacology

Chromatin-mediated alternative splicing in addiction.

Monday, April 3, 2023 3:00 PM Central Hosted by Dr. Nigel Atkinson

Heller Lab ↗

Abstract

The Heller Lab studies the gene regulatory mechanisms that underlie psychiatric disease. To approach this problem, we apply preclinical mouse paradigms of drug addiction and depression to define functionally relevant changes in chromatin modification that regulate gene expression and alternative splicing. Because the syndromes of addiction and depression persist long after cessation of the insult, chromatin remodeling is an attractive mechanism for such long-lasting effects and presents an intriguing target for therapeutic intervention. Today's seminar will focus on the recent discovery that histone methyltransferase in brain reward areas regulates cocaine reward behavior via regulation of alternative splicing.

David Linden, PhD

Johns Hopkins School of Medicine

The Solomon H Snyder Department of Neuroscience

Axon regeneration in the adult mammalian brain

Monday, April 10, 2023 3:00 PM Central Hosted by Drs. Hiroshi Nishiyama and Mike Mauk

David Linden ↗

Abstract

Recent work has shown that, contrary to dogma, serotonin and noradrenaline axons in the adult mammalian brain can regrow following a range of injuries. These regrown axons appear to be stable and functional.

Anastasia Kiyonaga, PhD

University of Caifornia, San Diego

Department of Cognitive Science

Flexible working memory for adaptive perception and action

Monday, April 17, 2023 3:00 PM Central Hosted by Dr. Joseph Dunsmoor

Kiyonaga Lab ↗

Abstract

Goal-directed cognition and behavior require the ability to keep information temporarily in mind. Humans ubiquitously rely on this ‘working memory’ to maintain multiple types of goals for use at multiple points in time. While we try to achieve these short-term goals, we also face distractions and other immediate demands in our environment. This talk will examine the principles of cognitive and neural function that dictate how working memory interacts with concurrent perceptual, attentional, and action demands. I will describe behavioral, neuroimaging, and brain stimulation studies to reveal how working memory survives (and supports) these competing demands. The talk will converge on the idea that working memory processes and representations can flexibly change with the combination of current demands.

Corey Ziemba, PhD

The University of Texas at Austin

Center for Perceptual Systems - Robbe Goris Lab

Confidence, uncertainty, and meta-uncertainty in perception

Monday, April 24, 2023 3:00 PM Central Hosted by Drs. Hiroshi Nishiyama and Robbe Goris

Goris Lab ↗

Abstract

Perceptual decisions are invariably accompanied by a feeling of confidence about whether they are likely to be correct. A standard account of the computational basis for this metacognitive ability has been elusive. We recently introduced a process model that proposes that subjects must estimate both the strength of the sensory signal and its uncertainty to compute confidence, and that both of these estimates are imperfect. We refer to the uncertainty of the perceptual uncertainty estimate as “meta-uncertainty” and find that its value can be recovered from standard confidence reporting tasks, varies across individual subjects, is stable over time, generalizes across some task domains, and can be manipulated experimentally. In ongoing work, we are exploring the neural basis of perceptual uncertainty estimates by recording from populations of neurons in the primary visual cortex of macaque monkeys performing a novel task where they are incentivized to report both a perceptual decision and the associated confidence on single trials.

Neal Amin, MD, PhD

Stanford University Dept of Psychiatry and Behavioral Sciences

Special Joint Seminar with Dell Med Psychiatry

At the intersection of human neuro-cellular diversity and disease

Monday, May 1, 2023 3:00 PM Central Hosted by Dr. Robert Messing

Amin at Stanford ↗

Abstract

In neuro-psychiatric disorders, populations of brain cell types become selectively vulnerable to cellular dysfunction, leading to varied outcomes ranging from autism to neurodegeneration. A more sophisticated understanding of how diverse brain cell types rely upon specialized gene regulatory programs promises to deliver insights into pathophysiological mechanisms. Furthermore, there is a great need for advanced neuro-cellular models to study features of brain development and dysfunction that are specific to humans. I will discuss my work in two areas: (1) the discovery of an RNA-mediated gene regulatory program necessary for motor neuron synaptogenesis and mammalian survival; and (2) the application of multiplexed single cell technology to diversify human brain organoids for the investigation of psychiatric-risk genetics. This work highlights the use of advanced technological approaches to investigate genes linked to neurological and psychiatric disorders and reveals a major role of RNA-mediated gene regulation in their pathophysiology.