Theory & Data Analysis Tools

Project Summary In vertebrate animals, the vestibular system (primarily known as the “balance system” of the brain) interprets head-movement and orientation signals to provide organisms with a sense of self-motion. The vital contribution of vestibular system to reflexive control of posture, gaze, and gait is well characterized; however, far less is known about the neural substrates underlying higher-order vestibular functions, such as the perception of self- motion and the awareness of one's orientation in space.

PROJECT SUMMARY The choroid plexus (ChP) comprises a network of cells that form a critical brain barrier that can mediate secondary damage in certain brain disorders and trauma. The Lehtinen lab has developed a suite of tools to study the ChP across development ex vivo and in vivo. This project applies imaging technology to study blood- CSF barrier permeability regulation at the cellular level.

Project Summary: The majority of lived experience depends on neural activity conveying sensory information about the world. Neural trauma and stroke are leading causes of disorders such as coma and spatial neglect, which severely damage visual experience, and there are no viable treatment options. Similarly, life saving medical treatments depend on the ability for general anesthesia to temporarily disconnect patients from the sensory world. Current anesthetics do so by inhibiting the entire brain, including the brainstem, which is a significant health risk.

PROJECT SUMMARY / ABSTRACT Persistent activity in neural circuits supports a variety of brain functions from motor control to navigation to perceptual decision-making. Correlational studies show significant variation in persistent activity patterns during different behaviors, suggesting that individual circuits perform flexible computations that depend on the context of ongoing brain activity and motor functioning. However, establishing the causal significance of this variability is difficult due to technical limitations in existing tools for precisely manipulating circuit dynamics.

Project Summary / Abstract Increased mammalian target of rapamycin (mTOR) signaling is a known cause of treatment resistant epilepsy. Pathological mutations to negative regulators of mTOR lead to hyperactive mTOR signaling and have been found in the forebrain and cerebellum of individuals with epilepsy. The cerebellum has recently been shown to contribute to the development of epilepsy. However, research in hyperactive mTOR induced epilepsy has almost exclusively been focused on the hypothalamus and forebrain structures.

Changes in the strength of GABAergic transmission is heavily influenced by posttranslational modifications and allosteric modulators like benzodiazepines and neurosteroids. O-GlcNAcylation (O- GlcNAc) is a post- translational modification that is tightly regulated by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), which add or remove the O-GlcNAc moiety of β–N-acetylglucosamine to Ser/Thr residues on proteins, respectively. Various neurodegenerative diseases like Alzheimer's disease (AD), and metabolic disorders like, diabetes exhibit dysregulated O-GlcNAc levels.

Project Summary Schizophrenia is a debilitating mental illness affecting an estimated 1% of the global population. Substance abuse comorbidity is common in a number of mental illnesses, including post-traumatic stress disorder, bipolar disorder, and schizophrenia, with nicotine being the most commonly abused substance. This comorbidity has several detrimental effects, including reduced quality of life and reduced efficacy of treatment.

Project Summary Sub-Cerebral Projection Neurons (SCPNs) are a clinically relevant neuron class that controls voluntary movement and whose loss in Amyotrophic Lateral Sclerosis and Fronto-temporal dementia or injury (e.g., damaged by spinal cord injury) leads to paralysis. Currently, there are no methods to replenish injured or lesioned SCPNs. A milestone in regenerative medicine is to utilize cellular reprogramming for brain and circuit repair. This approach uses developmental genes and identity maintenance pathways to switch one cell type to another to replenish vulnerable neuron types.

PROJECT SUMMARY/ABSTRACT Parental care is essential for offspring well-being and survival yet requires a significant invest from adults without immediate benefit, suggesting the existence of hard-wired mechanisms governing its control. Despite the importance of this evolutionarily controlled behavior, parental behaviors vary greatly between animals of different sex, physiological state, and genetic background.

PROJECT SUMMARY/ABSTRACT Humans have highly advanced cognitive abilities and motor skills, characteristics which are reflected in the enlarged size and cell diversity of our central nervous system (CNS). My overall goal is to profile and compare progenitor cell diversity in humans, non-human primates and rodents, and thereby identify the origins of increased cell diversity and size of the human CNS.