Neuroscience

Permanent URI for this collectionhttps://digital.lib.washington.edu/handle/1773/4894

Browse

Now showing 1 - 20 of 141

Discovering genetic regulators of pathological tau accumulation using a fluorescent C. elegans model of tauopathy
(2026-04-20) Han, Marina Soo-ahn; Kraemer, Brian C
Tauopathies comprise a group of aging-related neurodegenerative diseases that are pathologically characterized by aggregation of the microtubule-associated protein tau. Transgenic Caenorhabditis elegans serve as a powerful model organism to study tauopathy disease mechanisms, but moderating transgenic expression level has proven problematic. We generated a suite of transgenic strains with varying expression levels of photoconvertible Dendra2::tau. These strains exhibited expression level-dependent neuronal dysfunction that was modifiable by known genetic suppressors or an enhancer of tauopathy. Optical pulse-chase experiments reveal that Dendra2::tau turnover rate depends on Dendra2::tau expression level but not co-expression with the known tau enhancer TDP-43. Through a forward genetic screen using Dendra2::tau transgenic C. elegans, we identified hpo-10/LENG8 as a novel genetic enhancer of tau accumulation. Recently discovered functions of hpo-10/LENG8 in the mRNA export and quality control pathway suggests that this gene plays a translationally relevant role in neuronal health and tauopathy pathogenesis.
Acute and Consolidation Transcriptional Programs in the Central Amygdala Following Parabrachial Pain-circuit Activation
(2026-04-20) Pelos, Andrew; Palmiter, Richard; Stuber, Garret
The central nucleus of the amygdala (CeA) receives nociceptive input from parabrachial nucleus(PBN) neurons expressing the CGRP precursor encoded by the Calca gene, and plasticity at this synapse has been implicated in chronic pain development. Which CeA populations respond to parabrachial input, and how their transcriptional programs evolve from acute activation to consolidation, remains unclear. Here, we used single-cell RNA sequencing to characterize CeA GABAergic neuron responses after chemogenetic activation of CalcaPBN neurons at acute (D0.01, 30 minutes) and consolidation (D3, 3 days) timepoints. Analysis of 19,544 neurons resolved 21 clusters including 13 core CeA populations. Acute activation preferentially engaged C9, a population co-expressing Prkcd and Calcrl, which showed significant upregulation of immediate early genes including Arc, Egr1, and Egr4. Differential expression analysis revealed striking temporal asymmetry: D0.01 showed 1,872 differentially expressed genes (DEGs) with balanced directionality, while D3 showed 4,787 DEGs with a 25-fold bias toward downregulation. Suppressed genes included ionotropic receptors (Gria4, Gabra1), postsynaptic scaffolds (Camk2b, Shank3, Homer2), and the transcription factor Foxo3. Temporal overlap was minimal: just 15 genes sustained significance in C8 (Calcrl neurons) across both timepoints. Gene ontology analysis showed 87% of enriched terms were D3-specific, including synaptic plasticity regulation and negative regulation of long-term potentiation. These findings demonstrate that acute activation and early consolidation engage distinct transcriptional programs, with consolidation characterized by widespread suppression consistent with homeostatic refinement rather than simple potentiation. This molecular taxonomy identifies specific CeA populations and gene programs as potential intervention targets in the transition from acute to nociplastic pain.
Pericyte Remodeling in Health and Alzheimer's Disease
(2026-02-05) Nielson, Cara Diane; Shih, Andy
Pericyte loss is known to occur in aging and disease and has been linked to vessel regression through changes in capillary flow patterns. However, pericytes possess an intrinsic repair strategy to compensate for pericyte loss, as the surviving pericytes can remodel their processes to restore coverage of the exposed endothelium. Pericyte remodeling is impaired in the aged mouse brain, but we still have limited knowledge of the mechanisms that drive pericyte growth and how pericyte remodeling is affected by the amyloid-beta (Aβ) pathology characteristic of Alzheimer’s disease (AD). The platelet-derived growth factor (PDGF-B/PDGFRβ) signaling axis is an important pathway for pericyte recruitment to the vessel wall during development, and changes in PDGFRβ have been implicated in AD. As such, we hypothesized that PDGF-B/PDGFRβ signaling drives pericyte growth and that pericyte remodeling is diminished in mouse models of AD. To test these hypotheses, we performed longitudinal in vivo two-photon imaging in both 6 – 12-month PDGFRβCre;Ai14 mice and 12 – 18-month TgSwDI;PDGFRβCre;Ai14 mice with the Swedish, Dutch, and Iowan mutations of the APP gene. Optical ablation of brain pericytes was performed, and pericyte remodeling was measured over the span of one week while the potent and selective PDGFRβ inhibitor, SU16f, was delivered at 10mg/kg/day to the healthy adult mice. Interestingly, SU16f did not change the overall rate of pericyte growth compared to vehicle controls. However, processes with shorter baseline lengths grew faster in drug-treated animals, suggesting involvement of PDGFRβ in the remodeling process. In TgSwDI mice, we found that spontaneous pericyte loss occurred closer to the venules than the arterioles. Interestingly, this loss did not positively correlate with Aβ burden. Further, pericyte remodeling was significantly slower in TgSwDI mice, with the largest deficits found in cells closest to the venules. Spontaneous pericyte loss was associated with longer and more tortuous vessels indicative of vessel rarefaction. Mimicking capillary regression in 4 – 8-month wild-type mice reduced blood flow in venous outputs by ~50%, increased upstream blood flow heterogeneity, and induced chronic constriction of upstream transitional vessels, reducing flow to regions distant from the regression site. These results suggest a selective vulnerability of venous-associated pericytes in disease, further connect pericyte loss to cerebral hypoperfusion, and pinpoint PDGFRβ as a potential therapeutic target to promote pericyte coverage. Future studies will examine potential causes of pericyte loss in TgSwDI mice and investigate pericyte remodeling capabilities in conditional CNS pericyte-specific PDGFRβ mutant mouse lines.
Neural Cartography: Methods for Mapping the Structure of Neural Networks
(2026-02-05) Elabbady, Leila; Tuthill, John; Collman, Forrest
Recent advancements in volumetric electron microscopy (vEM) allow neuroscientists to map the nervous system at unprecedented scale and resolution. This offers an opportunity to unravel structural organization, cellular morphology, and connectivity, providing new insights into circuit function. This dissertation presents new tools for scalable analytical solutions and circuit analyses to extract testable biological insights from vEM wiring diagrams. In the first section, I utilize cell-body morphology and connectivity to train a hierarchical model for cell-type prediction in a cubic millimeter vEM dataset of mouse visual cortex. This method bypasses the need for complete cell reconstructions, is adaptable to multiple cell-typing schemes, and is computationally inexpensive. Further, this method produced predictions for nearly 100,000 cells with 91% accuracy compared to expert-labeled ground truth. These predictions, publicly available with a new feature set, can be used for unsupervised search of rare cell-types and demonstrated the surprising sufficiency of the somatic region for cell identification.In the second section, I reconstructed the wiring diagram of tactile sensory neurons in the fly ventral nerve cord to elucidate how spatial information is organized within somatosensory circuits, specifically regarding spatially targeted leg grooming. Using genetic labeling and vEM, I defined the foreleg somatotopic map. Downstream connectivity revealed 60 interneurons receiving substantial synaptic input exclusively from tactile neurons. These interneurons exhibit unique axonal projections, diverse dendritic morphologies, and distinct postsynaptic partners. Optogenetic experiments and kinematic analyses demonstrated that activating distinct interneurons initiates spatially guided grooming strategies consistent with our structurally derived receptive field predictions. From these results I propose a four-layer circuit where interneurons form distinct functional modules, each sampling a portion of the leg to elicit spatially targeted grooming. The third section extends this spatial mapping analysis to chemosensory information from the fly leg, using a similar approach to examine how a distinct circuit structure might also maintain spatial information for a different sensory system within the same body segment. Overall, this dissertation examines neural network maps broadly, quantifying structural variability in cell bodies and connectivity across large populations. It then zooms in on specific sensory circuits, exploring how their structural organization informs our understanding of neural computations.
Profiling the Heterogeneous Outcomes of Blast Trauma and Substance Use in Translational Mouse Models
(2026-02-05) Patarino, Makenzie Caterina; Schindler, Abigail
There is a complicated and bidirectional relationship between stress and substance use. Individuals who are diagnosed with a psychiatric disorder and a substance use disorder (SUD) tend to have a higher number of symptoms, more severe symptoms, decreased quality of life, and less responsiveness to treatment. Traumatic brain injury (TBI) is a unique form of stress in that it has both physical and psychological components. The most common type of TBI is mild TBI (mTBI), representing nearly 75% of all TBI diagnoses. Despite the label of “mild,” mTBI can result in behavioral and physiological symptoms that develop acutely and persist for years after the initial injury. Individuals who have a history of TBI show elevated rates of various substance use disorders, including alcohol, opioids, nicotine, cannabis, and psychostimulants. The Veteran population has a higher risk of psychiatric disorders and hazardous substance use, particularly alcohol, due to the frequency of exposure to traumatic events. Exposure to blast overpressure waves is the primary source of mTBI in military service members, and also commonly results in PTSD and chronic pain. Effective treatments and personalized clinical guidance is critical to improving outcomes for individuals experiencing comorbid stress and substance use disorders. Preclinical animal models are a valuable method for improving our understanding of the relevant mechanisms underlying the pathophysiological progression; however, there is currently a translatability crisis, in which potential treatments that have been effective in animal models are not effective in clinical trials. Therefore, it is critical to utilize translationally-relevant preclinical models and embrace the heterogeneity that they capture. The aim of this dissertation was to understand substance use patterns, stress and anxiety-like behavior, blast trauma, and the relationship between them in translational mouse models. First, I demonstrated the value of our novel Socially Integrated Polysubstance (SIP) system and the insights that it provides into individual intake patterns in group-house male and female mice. Again using the SIP system, I next quantified alcohol and opioid polysubstance use patterns in group-house male and female mice. Based on differences in behavioral phenotypes, I identified three clusters of mice with distinct alcohol and opioid dose preference and polysubstance use patterns. Building upon this, I used the SIP system to investigate how repetitive blast trauma influences various alcohol drinking patterns, as well as the chronic outcomes after blast trauma and alcohol use. This experiment revealed that only certain alcohol drinking patterns are predictive of biological outcomes and there are differential effects of repetitive blast exposure and chronic alcohol intake on glymphatic function and brain glucose metabolism. In the discussion, I consider various experimental parameters that are critical to designing translationally-relevant preclinical animal models. Finally, I cogitate on a number of future experiments that are still needed to help refine treatment options and identify therapeutic or lifestyle interventions at multiple stages of progression for individuals with comorbid stress and hazardous substance use.
Beyond Reflex: Nociception, Neural Circuits, and the Transformation of Threat into Memory in Drosophila melanogaster
(2026-02-05) Jones, Jessica Maia; Tuthill, John C
A fly flinches, jumps, runs—not randomly, but in a sequence carved by neurons that have been waiting for danger. For any animal, survival depends on knowing when the world has become dangerous—and reacting fast enough to avoid harm. This ability, called nociception, begins with specialized sensory neurons that detect mechanical, thermal, or chemical threats and ends with circuits that orchestrate escape and shape future behavior. In Drosophila melanogaster, nociception has been dissected in detail in larvae, but the adult system remains largely uncharted: how are its nociceptors wired, how do they drive different forms of escape, and how are their sensory properties tuned to the life of the adult fly? This thesis traces the anatomy and logic of escape in Drosophila melanogaster, revealing how a specific class of abdominal nociceptors initiates a spectrum of behaviors that begin with milliseconds of alarm and end with seconds of altered state.In this thesis, I combine connectomics, optogenetics, calcium imaging, single-cell RNA sequencing, and computational modeling to build a multi-level understanding of adult nociceptor function. I begin with a behavioral screen for neurons capable of driving aversion, focusing on a genetically defined subset of abdominal class IV multidendritic neurons (md). Connectomic reconstruction shows that md neurons project to two distinct downstream pathways: circuits for rapid, reflexive escape behaviors (running, jumping) and ascending circuits for arousal and behavioral modulation. Within the ascending pathway, a pair of inhibitory/peptidergic neurons emerges as a candidate mechanism for regulating both the magnitude and persistence of nociceptive responses, balancing sensitivity with stability. I next examine the molecular identity of md neurons. Single-cell RNA sequencing reveals a shift from the larval polymodal profile toward a mechanosensory-biased expression program, with strong enrichment of Piezo, ppk, and ppk26, and downregulation of thermosensory channels such as TrpA1 and Painless. Yet functional imaging reveals robust heat responses but no detectable mechanosensory activity, pointing to post-transcriptional regulation or context-dependent tuning. Together, these findings define the first steps of a complete circuit map for adult Drosophila nociceptors and show how parallel pathways coordinate rapid escape with longer-term state modulation. They also reveal that molecular identity does not always predict sensory function—reminding us that in neural systems, what a cell expresses and what it does are related, but not the same. This work offers both a detailed model for nociceptive control in a compact brain and a broader framework for thinking about how evolution balances urgency, persistence, and sensitivity in the face of danger. We also begin to discuss the ethical implications this type of study might present to us.
The Role of Transient Receptor Potential Canonical Type 6 (TRPC6) Channels in Regulating Ventral Tegmental Area Dopamine Neuron Physiology and Function
(2025-10-02) Bernstein, Mollie; Zweifel, Larry
Ventral tegmental area (VTA) dopamine (DA) neurons integrate neurotransmitter and neuropeptide signals to encode reward-related information. Extensive work from our laboratory and others has shown how specific subpopulations of VTA-DA neurons, defined by the expression of neuropeptide G-protein coupled receptors (GPCRs), regulate motivated behavior. These neuropeptide GPCRs activate signaling pathways that lead to increases in intracellular calcium ions, affecting cellular function and ultimately behavior. However, the mechanisms of these increases in intracellular calcium ions remain largely unexplored. Transient receptor potential canonical (TRPC) channels are a class of calcium-permeable ion channels, and our laboratory has identified TRPC type 6 (TRPC6) channels as the most abundantly expressed TRPC channel in VTA-DA neurons. Given strong evidence linking TRPC channel activation with neuropeptide receptor signaling, neuropeptidergic modulation of calcium signaling dynamics in VTA-DA neurons, and the widely established role of DA neurons encoding reward-related information, we hypothesized that TRPC6 channels are critical regulators of neuropeptidergic signaling pathways in VTA-DA neurons. To explore this, we disrupted TRPC6 channel function in DA neurons of the adult mouse VTA and performed ex vivo calcium imaging, whole-cell patch-clamp electrophysiology and in vivo fiber photometry during consummatory tasks. We demonstrate a novel mechanism by which TRPC6 channels regulate distinct aspects of neuropeptide receptor-activated calcium signals in VTA-DA neurons but make little contribution to the calcium dynamics associated with metabotropic neurotransmitter receptor signaling. Additionally, we show that TRPC6 channels regulate scalable reward valuation and consummatory behavior in a homeostatic state-dependent manner. Future studies will explore the single-cell calcium dynamics of TRPC6 channel-mediated signaling in vivo, the signaling complexes involved in the control of TRPC6 channel activation by neuropeptide receptors, and the role of other neuropeptidergic inputs to VTA-DA neurons that influence TRPC6 channel recruitment under varying homeostatic states.
The role of glia and CED-1/MEGF10 in C. elegans models of Parkinson's disease
(2025-10-02) Rojas, German; Singhvi, Aakanksha
Parkinson's disease (PD) is marked by progressive dopamine neuron degeneration, but the phagocytic receptors and cells that clear dopamine neuron corpses are unknown. Further, while other cell types like glia, skin, and muscle are also affected in PD, their role in disease progression is unclear. In my thesis project, I found that astrocyte-like CEPsh glia are neurotoxic in C. elegans PD models by regulating the neuronal dopamine biosynthesis enzyme CAT-2/tyrosine hydroxylase. I also identified epithelia and muscle as the phagocytes for dopamine neuron corpses. They engulf by recognizing phosphatidylserine on necrotic-like neuron corpses via the conserved receptor CED-1/Draper/MEGF10. Loss of ced-1 protects from loss of dopamine neurons but does not protect against the impairment of associated dopaminergic behaviors. Altogether, my thesis work provides evidence for the involvement of glia, muscle, and epithelial cells as potential mediators of dopamine neuron degeneration. Thus, my thesis work suggests that PD may be a disease of multi-organ dysfunction and could inform future therapeutic interventions.
Pleiotropic functions of TAOK2 and its dysregulation in neurodevelopmental disorders
(2025-10-02) Byeon, Sujin; Yadav, Smita
Thousand and one amino acid kinases (TAOKs) are relatively understudied and functionally pleiotropic protein kinases that have emerged as important regulators of neurodevelopment. Through their conserved amino-terminal catalytic domain, TAOKs mediate phosphorylation at serine/threonine residues in their substrates, but it is their divergent regulatory carboxyl-terminal domains that confer both exquisite functional specification and cellular localization. In this work, we focus specifically on diverse functions of TAOK2 in the context of neurodevelopment and neurodevelopmental disorders. TAOK2 is the only member of the TAOK family with two coiled coiled domains instead of three, and the canonical isoform, TAOK2α, has a unique endoplasmic reticulum (ER) targeting domain and microtubule binding domain functioning to tether ER to microtubules. Its spliced isoform, TAOK2β, is less understood. The precise mechanisms underlying the role of TAOK2 in neurodevelopment and neurodevelopmental disorders are not clearly understood. Following up on previous work showing that TAOK2 phosphorylation of cytoskeletal protein Septin 7 is critical for dendritic spine maturation, in Chapter 2, we identify 14-3-3 proteins as downstream interacting proteins important for maintaining this phosphorylation. We have also identified changes in primary cilium length, trafficking, and signaling as potential mechanisms underlying copy number variation of 16p11.2, a genomic locus in which TAOK2 resides, in Chapter 3. Further, in Chapter 4, we lay preliminary work showing that autism associated TAOK2 mutations differentially affect the catalytic activity and localization. In summary, this work elucidates how TAOK2 contributes to neurodevelopment and associated disorders through its pleiotropic functions.
The midbrain reticular formation in flexible visual decision-making
(2025-08-01) Shaker, Jordan Robert; Steinmetz, Nicholas
A hallmark of mammalian behavior is the ability to rapidly remap actions in response to sensory stimuli depending on internal representations of the environment. Flexible visual decisions are thought to be computed within recurrent interactions across diverse brain circuitry in the frontal cortex, basal ganglia, and midbrain. However, the precise regions involved and their computations remain unclear. Previous work has found that a large and poorly understood structure of the midbrain, the midbrain reticular formation (MRF), contains similar task activity patterns to well-established decision regions and connects extensively with them. Open questions include whether the task dynamics in MRF reflect motor processing versus abstract task rules as well as how structure and function organize within the MRF. In this dissertation, we dissect the organization of MRF and demonstrate a role for MRF in abstract context computation using a novel flexible decision-making task, large-scale electrophysiological recordings, modeling of task behavior and neural population dynamics, and single neuron morphological reconstructions. In Chapter 1, we first review the approaches to studying flexible visual decision-making in the lab and the current understanding of the regions and computations involved. We then discuss what is currently known about MRF’s functional and anatomical characteristics and examine historical perspectives on its role in contextual processing. Next, we introduce our novel flexible decision-making task and show that mice achieved high levels of performance by integrating an abstract context belief variable with visual stimuli to remap stimulus-action associations (Chapter 2). We performed dense electrophysiological recordings within MRF and established nodes of the flexible-decision making circuitry and find that MRF, in a network with the superior colliculus (SC), secondary motor cortex (MOs), and caudoputamen (CP), maintained a baseline representation of context which putatively enabled flexible remapping by shifting action attractor dynamics between contexts (Chapter 3). In Chapter 4, we record from both trained and task-naive mice while passively presenting stimuli and find that task-specific visual stimulus representations appear throughout MRF as a result of task learning. Then, we examine the spatial distribution of context-coding neurons and cortical inputs across MRF, revealing that context-coding neurons and cortical axon terminals both contain non-uniform distribution patterns and are spatially aligned (Chapter 5). Altogether, our results establish MRF as a key node in the circuitry underlying flexible visual decisions and provide fundamental insights into how the brain processes contextual information to flexibly update responses to environmental stimuli. In Chapter 6, we integrate prior literature with the findings in this dissertation to update current theories of MRF and discuss future work to build upon and test these theories.
Neuropeptidergic Modulation of Canonical Reward Circuitry Underlying Escalation of Cocaine Consumption
(2025-08-01) Gordon-Fennell, Lydia; Phillips, Paul EM
Substance use disorder (SUD) and its related harms are a major public health concern in the United States and across the globe. Pharmacological treatment options are limited or nonexistent for many types of SUDs. Harm reductionist approaches to SUD, including pharmacological and non-pharmacological, have proven more effective at reducing individual and society impact of SUD than traditional abstinence only based approaches. However, our incomplete understanding of the neurobiology underlying the progression and sustainment of SUD hinders the development of new, more effective treatment. This dissertation focuses specifically on one specific SUD-like phenotype characterized by an increase in drug consumption over time (termed escalation). Preventing escalation and/or reversing escalation decreases harm through decreasing the likelihood of infection, overdose, and potential monetary/social loss of the individual with a SUD. Understanding the neurobiological basis of escalation will inform future therapeutic strategies. The neurotransmitter dopamine has a long history of being implicated in addictive drugs and there is evidence suggesting its causal relationship to escalation. Here, I will investigate two systems – dynorphin / kappa opioid receptors and corticotropin releasing factor – in their ability to modulate drug consumption, specifically escalation of cocaine self-administration. Both of these systems are capable of modulating dopamine, modulating each other, and have been implicated in the negative affect and withdrawal symptoms of SUD that are theorized to escalate drug consumption. Through pharmacological and gene editing techniques, I demonstrate in Chapter 2 that the kappa opioid receptor system, specifically expressed in ventral tegmental area neurons, is necessary for escalation of cocaine consumption. Using the same techniques, I demonstrate in Chapter 3 that the corticotropin releasing factor system in the nucleus accumbens, specifically CRF-R1, is not necessary for the development nor sustainment of escalation of cocaine consumption. Additionally, in Chapter 4 I provide a survey of cocaine self-administration in female versus male rats and provide evidence that this behavioral paradigm is capable of producing the SUD-like phenotype of escalation equally in females and males. These data provide further evidence for the dynorphin/kappa system to contribute to the β-process of the opponent process theory of SUD, independent of corticotropin releasing factor modulation through CRF-R1. I specifically implicating the dynorphin/kappa system of ventral tegmental area neurons that project to the nucleus accumbens. In the discussion, I theorize about downstream mechanisms and future experiments to investigate the temporal dynamics of dynorphin in the nucleus accumbens and its potential to modulate dopamine release during cocaine self-administration to escalate drug consumption.
Assessing whether human oligodendrocytes go senescent: a cell culture and transcriptomic interrogation of human white matter
(2025-05-12) Voth, Joseph; Keene, Christopher D.
White matter (WM) atrophy is an early sign of Alzheimer's Disease pathophysiology. However, our understanding of the main cell type that comprises white matter, the oligodendrocyte (OL), is far less understood than other neural cell types. Senescence is a phenotype associated with aging where damaging stimuli cause permanent cell cycle arrest. To date, it is unclear whether OLs become senescent or not. Understanding OL functions in both WM and gray matter (GM), and whether OLs become senescent, will help incorporate these cells into the complex physiology of the human brain. We developed human OLs from induced-pluripotent stem cells and found little evidence of senescence after exposure to typical senescence-inducing agents. Next, we generated a single nucleus RNA sequencing dataset on human WM, using spatial transcriptomics provide further information. We integrated our WM OLs to an overlapping dataset on GM and identified that GM OLs are producing more machinery for synapse formation and neurotransmitter cycling, while WM OLs are producing more immune and autophagy transcripts. Further, we identified a unique OL phenotype in high AD pathology donors with elevated transcripts related to cytokine production, cytoplasmic chaperone proteins, DNA damage repair, and ferritin accumulation. Together, we have identified a possible senescent OL phenotype and generated a highly valuable resource for further studies.
Follow your nose: the computational role of olfaction in spatial memory and navigation
(2025-01-23) Sterrett, Scott C; Fairhall, Adrienne L; Gire, David H
Olfactory stimuli permit perception of distant objects and odors are intimately connectedto memories. The brain must integrate olfactory stimuli with the time and place that they were experienced, but the brain lacks receptors for time or place. How does the olfactory system link odors to spatial memory in order to adaptively navigate complex environments? We find that the mouse olfactory system is modulated by multiple aspects of the animal's environment as early as the olfactory bulb, the first synapse in the olfactory system. The spiking activity of olfactory bulb neurons encodes the sniffing behavior at both a subsecond, intersniff timescales as well as longer timescale breathing rhythms. Additionally, we find that olfactory bulb neurons represent an animal’s allocentric location. Through task-trained recurrent neural network simulations, we hypothesize that this olfactory-spatial interaction depends on the behavioral demands of a simulated searcher to adaptively support localization. These findings provide novel insights into the nature of olfactory perception in awake behaving animals that motivate a more integrative approach to the study of olfactory physiology.
Motion Sensitivity in Center-Surround Receptive Fields of Primate Retinal Ganglion Cells
(2024-10-16) Appleby, Todd; Manookin, Michael B; Rieke, Fred
Primate visual perception is built on the 20-25 parallel pathways in the retina that carry infor-mation of the visual world to the rest of the brain. Each parallel pathway is represented by a unique type of primate retinal ganglion cell, the outputs of which are formed by a collection of upstream retinal circuits. While each primate retinal ganglion cell type maintains its own unique function, all retinal ganglion cells share a common receptive field structure: an excitatory center enveloped by a suppressive surround. The center-surround receptive field functions to enhance spatial structures likes edges, and in some ganglion cell types contributes to the encoding of color and temporally modulated inputs. Visual motion is well studied across many cortical and subcortical regions of the primate visual system, but our knowledge of how visual motion affects encoding properties of retinal ganglion cells is limited. This thesis aims to characterize visual motion sensitivity in a subset of primate retinal ganglion cell types from the perspective of the classical center-surround receptive field. Our results fall along two major themes. First, that the receptive field centers of some ganglion cell types are far more sensitive to motion of approaching objects than receding ob- jects (Chapter 2). Second, in some ganglion cell types, the presence of motion in the receptive field surround shifts the center-surround relationship from antagonistic to facilitatory (Chapter 3 and 4). Our work suggests that neural inputs to primate retinal ganglion cells are activated dynamically as visual contexts shift, particularly for contexts that involve visual motion. Overall, we demonstrate that the primate retina has the computational complexity required for motion sensitivity that was previously considered to be present only in the primate cortex.
NEURAL DYNAMICS OF COGNITIVE FLEXIBILITY: META-RPE SIGNALING WITHIN A PRELIMBIC CORTEX-VENTRAL TEGMENTAL AREA CIRCUIT EXPEDITES CONTINGENCY DEGRADATION DURING COGNITIVE FLEXIBILITY
(2024-10-16) Hjort, Madelyn M; Stuber, Garret D
Although tightly associated with prefrontal cortex (PFC), concrete cognitive flexibility signals have historically been ill defined. One common test of cognitive flexibility involves reversal learning, where the contingencies of discrete learned cues are enhanced or degraded, and an individual subsequently must flexibly remap their behavior. This work presents meta-RPE (mRPE), a cognitive flexibility signal that peaks in the middle of reversal behavior and represents the average of repeated, concentrated errors over many trials. Allowing mRPE to modulate canonical single-trial reward prediction errors (RPEs) expedites reversal learning and fits observed animal behavior better than models with static learning rates. Using novel statistical and imaging methods, this work identifies a subpopulation of neurons in prelimbic cortex (PL), a PFC subregion, that selectively encode a contingency degradation-related mRPE signal and can directly modify RPE via preferential representation in projections to VTA. Otherwise stable PL dynamics across reversal suggest the mRPE signal is unlikely attributable to representational drift. Dopaminergic innervation to PL does not predict the mRPE signal, instead representing a contingency elevation mRPE signal from elsewhere in the brain. Deriving mRPE and identifying its neural correlate in the PL-VTA circuit represents a quantitative advance in the field’s understanding of cognitive flexibility signaling within the prefrontal cortex.
A premotor connectome reveals circuits for rapid, flexible, and precise wing control in Drosophila
(2024-09-09) Lesser, Ellen; Tuthill, John
The nerve cord processes information from sensory systems and controls muscles. Thesecomputations are implemented by neural circuits: networks of neurons with synapses between them. This project seeks to gain insight into features of neural circuit organization that allow an animal to rapidly respond to a changing environment. Even a fly, which has a fraction of the number of neurons as a human, has neural circuits that give rise to highly precise control of muscles informed by complex sensory inputs. This precision is especially important when a fly is in flight, as the animal actively controls its path by making small adjustments in muscles that controls the wings. To gain insight into the anatomical circuits that coordinate flight, we reconstructed neurons in sensorimotor circuits that control the wing. We identified muscle targets of all the wing motor neurons, analyzed the synaptic weights between premotor neurons and motor neurons, and mapped sensory axons to the structures on the wing that they innervate. By analyzing wing circuitry alongside leg circuitry in the same animal, we found evidence that premotor circuit organization is dictated by the biomechanical properties of the joint it controls. This project demonstrates that the synaptic structure of sensorimotor circuits can vary even within the same animal. We propose that the specific circuit architectures we observe correspond to the biomechanical constraints of different types of joints. By analyzing circuits at the level of single neurons and synapses, this work seeks to expand our understanding of the many ways sensorimotor circuits can be organized.
Speed of Forgetting: A Computational Biomarker and Early Indicator for Memory Impairment
(2024-09-09) Hake, Holly; Stocco, Andrea
In our increasingly digital world, medicine and healthcare must advance accordingly. This work validates a model-based tool for quantifying forgetting and capturing general biological processes behind abnormal memory impairment. We introduce an online assessment tool for early detection of memory impairments. By using the computational biomarker 'Speed of Forgetting', our system transforms memory assessment with an easily interpretable and repeatable model. It detects impairments in just 8 minutes of online interaction, far surpassing traditional methods that require up to 3 hours in a clinical setting. This metric advances proactive memory care, enabling broad and affordable cognitive health monitoring across diverse populations.
In-Vivo Characterization of S-cone Topography Across the Human Macula
(2024-09-09) Schleufer, Sierra Ashley; Sabesan, Ramkumar
Patterns of S-cone topography, the arrangement of short-wavelength sensitive photoreceptors in the retina, have long fascinated vision scientists. Many aspects of human S-cone topography are not well understood due to paucity of data. In this body of work, we examined S-cone topography from ROIs spanning the central ~1-12deg of the retina in two subjects. This comprises the largest dataset of human S-cone topography period, let alone within individuals. We developed novel approaches to characterize the semi-regular topography of S-cones, which led to the discovery of a novel pattern: that they are unlikely to be found within two concentric rings of cones surrounding S-cones. In addition, we found that S-cones are likely to have significantly far neighbors in the central retina (< 3 deg), and likely to have significantly near neighbors more peripherally. In total, this work provides a number of new analytic and simulation methods that show promise for the study of cone topography, and reveals robust insights into the patterns underlying human S-cone topography.
Rage against the machine: advancing aggression ethology through machine learning
(2024-09-09) Goodwin, Nastacia L.; Golden, Sam
Aggression is a highly conserved behavior and exists along a spectrum from adaptive to maladaptive. Adaptive aggression can serve to protect mates, territory, and resources. Maladaptive aggression, however, can present as escalated and uncontrolled, and can occur comorbid with neuropsychiatric disorders including autism spectrum disorders, post-traumatic stress disorder, and intermittent explosive disorder. Inappropriate aggression seeking is detrimental to both individuals and society, and current treatment options are largely ineffective, or associated with significant side effects (Coccaro et al. 2009; Carlson et al. 2010; Frogley et al. 2012; Khushu and Powney 2016). In the clinical literature, aggression is typically delineated into instrumental, reactive (fight or flight), and appetitive (rewarding) phenotypes. Preclinically, there is a long history of research involving reactive aggression, but a much smaller body of work only in males examining the neurobiology of appetitive aggression. The goal of this dissertation was to further develop preclinical models of appetitive aggression in mice by understanding the different behavioral and whole-brain activation patterns between the sexes, and by directly comparing appetitive and reactive aggression phenotypes. A significant portion of my work in this arena has involved developing a machine learning based platform for high throughput and consistent scoring of aggression behaviors - Simple Behavioral Analysis (SimBA). Importantly, I posit that machine learning based behavioral detection paired with artificial intelligence explainability techniques allows users to objectively quantify and share behavioral classifiers in an RRID-like fashion. Using this platform, I have discovered that while both males and females exhibit reactive aggression, males but not females show appetitive aggression. I examined the neural correlates of this behavioral sex difference using whole-brain c-fos activity mapping, identifying a potential network inhibiting appetitive aggression in females. In males, I further identified the lateral septum as a potential locus of differential control of reactive and appetitive aggression. Ultimately, this dissertation indicates that reactive and appetitive aggression are neurally dissociable processes, with an inhibitory network in females gating appetitive aggression.
Characterizing Dynamic Protein Interactions That Mediate mTOR Signaling in Shank3-deficient Neurons during Homeostatic Scaling
(2024-09-09) Wehle, Devin Taylor; Smith, Stephen EP
The mTOR signaling cascade is a central signaling pathway that has been implicated in autism spectrum disorder (ASD). We have developed a Quantitative Multiplex Immunoprecipitation (QMI) panel to analyze changes in the mTOR protein interaction network (PIN). We observed extensive PIN one hour after the addition of fresh media despite phosphorylation changes occurring after five minutes. Various mTOR/ERK inhibitors acted on subsets of the PIN, referred to as modules, that responded differently to each inhibitor. Homeostatic scaling, induced by TTX or BIC treatment in cultured neurons, caused dissociations in different combinations of modules depending on scaling direction. In Shank3B-/- neurons, the scaling-responsive modules were pre-active at baseline and their response range was warped during scaling. Shank3B-/- neurons also produced an exaggerated response to treatment with the mTOR inhibitor Rapalink-1. These data provide the basis for understanding the relationship between mTOR signaling, synaptic scaling, and autism spectrum disorder.

Browse

Recent Submissions