Training

PROJECT SUMMARY Postnatal sensory experience has a profound effect on the maturation, composition, and connectivity of cortical cell types, but systematic analyses of these changes have not yet been feasible. This lack of methods for systematic analysis had made it difficult to define principles in how neural activity re-wires brain circuits and whether connectivity changes precede or follow molecular changes in brain cell types.

Project Summary Many social behaviors, such as defense and aggression, are innate- requiring no prior experience to be expressed and presumably ‘hardwired’ into neural circuits. Interestingly, however, these ‘hardwired’ behaviors vary in expression among individuals and can be altered by experience. What are the neural circuits and mechanisms that support such flexible expression of innate behaviors?

Abstract In recent years, the number of neurons that we can record simultaneously has seen an exponential increase, presenting a daunting challenge: how do we analyze these complex and high-dimensional datasets to gain insight into how neural circuits perform computation? Tools from dynamical systems theory have successfully unraveled the computational machinery of artificial recurrent neural networks (RNNs) trained to perform goal-directed tasks.

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.