Store-operated Ca2+ entry (SOCE) is a principal mechanism for generating cellular Ca2+ signals. Store-operated Ca2+ release-activated Ca2+ (CRAC) channels serve an essential role in generating Ca2+ elevations needed for transcriptional, enzymatic, and secretory effector cascades in many cell types. CRAC channels, comprised of the ER Ca2+ sensor STIM and the...
Birds such as the barn owl and zebra finch are known for their remarkable hearing abilities that are critical for survival, communication and vocal learning functions. A key to achieving these hearing abilities is the speed and precision required for the temporal coding of sound; a process heavily dependent on...
New neurons are continuously produced in the subgranular zone of the dentate gyrus of the hippocampus throughout life. These newborn dentate granule cells (DGCs) undergo a stereotyped process of morphological and functional maturation during the first few weeks after differentiation that recapitulates some aspects of postnatal neuronal development. The inhibitory...
The brain is known to shrink in normal aging or neurodegenerative disease and yet the neurobiological underpinnings of the cortical atrophy remain elusive. The structural changes that represent cortical atrophy can be measured during life using the reliable and quantitative method known as magnetic resonance imaging (MRI). Primary progressive aphasia...
Frontotemporal dementia (FTD) encompasses a group of neurodegenerative disorders characterized by cognitive and behavioral impairments. Heterozygous mutations in progranulin (PGRN) cause familial FTD and result in decreased PGRN expression, while homozygous mutations result in complete loss of PGRN expression and lead to the neurodegenerative lysosomal storage disorder neuronal ceroid lipofuscinosis...
For years, neuroscientists have strived to understand memory consolidation, where salient memories are sorted and organized into distributed cortical networks for long-term storage. A large body of sleep research suggests that slow-wave sleep is an optimal opportunity for memory consolidation, and that consolidation is driven, at least in part, by...
After stroke, inappropriate muscle activity phasing during the locomotor cycle is a key contributor to locomotor impairment. Muscle phasing has been shown to vary between behaviors post-stroke, but the degree to which individuals can voluntarily modulate activity is unclear. This dissertation consists of a series of three studies that investigate...
The cerebellum is involved in sensorimotor processing and motor control in the brain. What has been found across many species for many behaviors is cerebellar Purkinje (Pkj) cells and cerebellar nuclear (CbN) cells show activity that is related to and predictive of movements. Less is known about how patterns of...
Identifying key molecular mechanisms and targets for therapeutic development in sporadic neurodegenerative diseases has been challenging. Therefore, in-depth investigation of genetic forms of disease can provide valuable insight into pathogenic disease mechanisms. The discovery of genetic forms of Parkinson’s disease (PD) has highlighted the importance of the autophagy/lysosomal and mitochondrial/oxidative...
Rhythmic fluctuations of electrical activity in the brain provide insights into the proposed mechanism by which we encode experiences and then maintain, forget, modify, and retrieve them. Yet there is still much to learn about how neural oscillations relate to memory function. The purpose of this research is to discover...
Frontotemporal Dementia (FTD) and Amyotrophic Lateral Sclerosis (ALS) are two devastating neurodegenerative diseases that affect 100,000s of people globally. They have a severe adverse impact on society, yet there are currently no early diagnostic tools or disease-modifying therapies available. Despite their clinical heterogeneity, evidence points to these diseases being on...
Individuals following a stroke suffer from a host of movement impairments that affect the upper extremity. Hand use is often significantly compromised, especially in individuals with more severe impairments, which makes it difficult for individuals to participate in activities of daily living. One of the major goals of rehabilitation is...
We have a remarkable ability to perform complex, coordinated movements without much conscious effort. In addition to the computations required to generate commands for muscles, a key aspect of coordinated motor control is incorporating sensory feedback about the movement. One of the most important feedback routes is through proprioception, the...
The presence of subjective cognitive decline (SCD) among cognitively normal-for-age older adults is increasingly hypothesized to represent a preclinical stage in the development of Alzheimer’s dementia (Jessen et al., 2014). This project aimed to characterize this construct with regard to its cognitive, motor, emotional, and functional features. The first study...
Contactin associated protein like 2 (CNTNAP2) has emerged as a prominent susceptibility gene implicated in multiple complex neurodevelopmental disorders, including autism spectrum disorders (ASD), intellectual disability (ID), and schizophrenia (SCZ). The presence of seizure comorbidity in many of these cases, as well as inhibitory neuron dysfunction in Cntnap2 knockout (KO)...
Episodic memory provides a means by which we are able to reflect on the past, make decisions about the future, and form a learned identity. Even subtle changes to our memory can have a detrimental impact on our daily lives. Memory declines as we age, and clinically salient impairment is...
Motor planning is fundamental to the performance of everyday reaching movements. The influence of planning is not limited to voluntary movements but extends to involuntary movements initiated in response to sensory stimuli, such as postural perturbations applied to the arm. Stroke alters voluntary reaching and the involuntary response to perturbations,...
One of the most fascinating observations in the brain is that the neural connections change with experience and this phenomenon is called synaptic plasticity. Patterns of activity or neuromodulators can acutely induce changes in the synaptic strength in the brain. My thesis is focused on understanding the mechanisms of plasticity...
This thesis focuses on the development of a cochlear implant (CI) that uses photons to stimulate surviving auditory neurons in severe-to-profoundly deaf individuals. The benefit of optical over electrical stimulation is its spatial selectivity with the potential to create significantly more independent channels to encode acoustic information and likely enhances...
We perform many movements every day without much deliberation. However, moving can be seen as a form of decision-making since one of many possible movements must be selected and executed. The decision-making processes that underlie movements are influenced by various factors, including sensory perception, energetics, time, perceived rates of failure...