The brains of humans and animals have the amazing capability of extracting abstract relationships between external stimuli efficiently. Knowing such regularities helps us compute and react to novel information flexibly without prior experience. The olfactory system is no exception. Animals need to infer commonalities across different odors sharing similar meaning,...
Parkinson's disease (PD) is a movement disorder that arises following the degeneration of dopamine-producing neurons of the substantia nigra pars compacta (SNc). Patients experience a host of limiting motor symptoms such as rigidity, tremor, and a paucity of controlled movement generation. These symptoms often correspond with a predominance of abnormally...
The cerebellum contributes to movement initiation, execution, and adaptation. Primary cerebellar neurons receive synaptic inputs related to sensory stimuli and motor commands, leading to modulation of their firing. Furthermore, synaptic input differs substantially between cerebellum-dependent behaviors. I have made voltage- and current-clamp recordings from Purkinje and eurydendroid neurons in the...
Mounting evidence indicates that known schizophrenia susceptibility genes regulate dendritic spines supports the model that perturbations in the molecular network underlying spine plasticity are crucially involved in the pathogenesis of schizophrenia. The Rac1- and RhoA-guanine nucleotide exchange factor (GEF) kalirin is critical for spine morphogenesis on cortical pyramidal neurons, and...
The mammalian retina harbors more than 30 output channels, each playing a distinct role in processing visual images. A comprehensive understanding of the retinal code primarily relies on the functional knowledge of individual output neurons or retinal ganglion cells (RGCs). Despite recent technical advances in imaging and genetics, the function...
A central question in neuroscience is how the brain plans movements. Here, I apply neural data analysis and machine learning methods to better understand both eye and arm movement planning, in particular focusing on naturalistic settings. First, I built encoding models to investigate the factors that led to neural activity...
Following a stroke, precise, individuated control of single joints is often replaced by highly stereotyped patterns of multi-joint movement, due to a loss of independent joint control, which can negatively impact functional use of the paretic arm. Despite the debilitating nature of this impairment, the precise underlying neural mechanisms remain...
Totipotent cells have the highest developmental potential and can only be created by nuclear transfer into oocytes. Identities of maternal factors that can induce this reprogramming remain a mystery. In this report, we demonstrate induction of totipotency on mouse embryonic stem cells by introducing six factors, Hist1h2aa, H3f3b, H1foo, p-Npm2,...
Psychosocial stress is part of everyday life, and while ubiquitous, stress plays a huge role disease development and treatment. Though the stressor’s intensity, predictability, and frequency (acute vs chronic) are important determinants of disease development, interactions with one’s genetic and epigenetic make-up also play a causal role. Major Depressive Disorder...
In vivo, substantia nigra pars compacta (SNc) dopaminergic neurons exhibit three spiking patterns – irregular, regular, and bursting. These distinct modes of activity are thought to underlie the different roles that dopamine (DA) plays in target structures within the basal ganglia. In particular, burst spiking in SNc DA neurons is...
As neuroscience seeks to understand larger, more complicated systems and behaviors, we will require neural recording techniques that can monitor the activity of neurons across the whole brain. The unparalleled data-storage capabilities of DNA, combined with fast, genetically encodable DNA polymerase-based sensors, would allow for "ticker tape"-like recordings of neurons...
Large projection neurons of the cerebellar nuclei (CbN cells), whose activity generates movement, are inhibited by Purkinje cells and excited by mossy fibers. The high convergence, firing rates, and strength of Purkinje inputs predict powerful suppression of CbN cell spiking, raising the question of what activity patterns favor excitation over...
Habits are actions taken without conscious consideration of a goal. The distinction between habits and conscious, goal-directed actions has been made for millennia. Only comparatively recently, however, have results from biological psychiatry and neuroscience begun to shed light on the existence of separable neural circuits that underlie our intuitive perception...
Saccharomyces cerevisiae contains several epigenetic elements known as yeast prions. Our laboratory discovered the yeast prion [SWI+], whose protein determinant is Swi1, a subunit of the SWI/SNF chromatin-remodeling complex. Formation of [SWI+] results in abolishment of multicellular features and a partial loss-of-function phenotype of non-glucose carbon source usage. Our laboratory...
The mouse visual system has recently been shown to possess many of the properties observed in the visual systems of the classically studied carnivores and primates. An ever-expanding genetic toolkit has given researchers who study vision in mice many advantages unavailable in other species.
In this thesis I study the...
Worldwide, youth living with perinatally-acquired human immunodeficiency virus (PHIV) are at increased risk for cognitive dysfunction and developmental delay. Effects of the virus, chronic inflammation, and combination antiretroviral therapy (cART) during critical periods of brain development may disrupt normal cognitive development. Neuroimaging studies using structural magnetic resonance imaging (sMRI) allow...
The form and function of neural circuits are shaped by experience during critical periods of development. Recently, our lab discovered an important outcome of critical period plasticity in the visual system, namely, binocular matching of orientation preference, whereby initially randomly aligned orientation preferences become matched in individual cells. Following this...
The over-a-decade quantitative study of the flexion synergy has provided concrete evidence that the stereotypical movement coupling of shoulder abduction with elbow flexion and wrist/finger flexion (i.e. flexion synergy) significantly affects the ability to perform functional upper extremity movements that are essential for activities of daily living (e.g. reach-to-grasp an...
In Amyotrophic Lateral Sclerosis (ALS), spinal motoneurons degenerate in the order of large motoneurons that innervate fast and fatigable muscle fibers to small motoneurons that innervate slow muscle fibers (Pun et al. 2006). This order of degeneration is peculiar in that it is in direct opposition to the normal order...
Our capacity to share ideas through content is the paramount feature of the human brain. All of our species’ advanced communication and coordination fundamentally relies on our ability to “think alike,” yet the parallels between our brains are grossly understudied, especially regarding engagement with dynamic audiovisual stimuli. Therefore, we present...
The floor plate (FP) is a ventral midline organizing structure of the developing neural tube that provides positional information using morphogen concentration gradients towards the production of diverse neuron types. In caudal regions the FP is non-neurogenic unlike the mesodiencephalic region of the FP that is highly neurogenic, and is...
Dopaminergic neurons in the substantia nigra pars compacta are richly innervated by GABAergic neurons. The postsynaptic effects of GABA on SNc DA neurons are mediated by a mixture of GABAA and GABAB receptors. Although activation of GABAA receptors inhibits spike generation, the consequences of GABAB receptor activation are less well...
Age-related cognitive deficits are observed in both humans and animals. Yet, the molecular mechanisms underlying these deficits are not yet fully elucidated. In aged animals, a decrease in intrinsic excitability of pyramidal neurons from the CA1 sub-region of hippocampus is believed to contribute to age-related cognitive impairments, but the molecular...
Loss of inhibitory control from descending serotonergic (5-HT) fibers deregulates the excitability of spinal motoneurons and interneurons following spinal cord injury (SCI). Exaggerated synaptic activity triggers long-lasting excitatory postsynaptic potentials (long EPSPs) in hyperexcitable motoneurons to ultimately drive muscle spasms at the chronic stage of SCI. Deep dorsal horn (DDH)...
Fetal alcohol spectrum disorder (FASD), the result of fetal alcohol exposure (FAE), affects 2-11% of children worldwide with no treatments in sight. In my thesis work, I aimed to identify underlying biological mechanisms of the FAE-induced hippocampus-based cognitive deficits that would lead to identify potential treatment targets to reverse the...
Amyotrophic lateral sclerosis (ALS) is characterized by progressive motoneuron loss. Autopsy from thoracic spinal tissues of sALS patients revealed a significant loss of large motoneurons while medium and small motoneurons were relatively unaffected. Using two-photon microscopy, we observed a soma hypertrophy of neonatal motoneurons in mice overexpressing mutant human G93A-superoxide...
The striatum is a subcortical nucleus that regulates a number of complex activities ranging from voluntary action selection to the subconscious formation of habit. The coordination of these operations is mediated by the principle cells of the striatum, spiny projection neurons (SPNs). SPN activity is dictated by a confluence of...
Chronic pain is a prevalent and under-treated condition that remains a mystery to the medical system and a major social and economic problem. Unfortunately, there is no single treatment superior to others for relieving chronic pain. While recent scientific discoveries have provided us with functional and anatomical brain biomarkers of...