To survive, animals, including human beings, have developed an amazing ability to learn the constantly changing environment. Specifically, detecting specific odorants in a noisy, variable background is crucial for finding food and water, mating, and avoiding potential dangers. For this purpose, rodents have developed an olfactory system that is powerful...
Maneuvering your limbs requires both accurate commands for how to move, and accurate feedback of their true movements. Conventional prosthetic arms currently lack this sense of proprioceptive feedback, which can make daily tasks difficult without close visual monitoring. Although studies have successfully provided artificial proprioceptive feedback to improve control, this...
Neurons are sensitive to the mechanical properties of their environment and show better growth, survival and differentiation when they are cultured in soft environments with mechanical properties similar to those of the brain compared to other tissues. Within the central nervous system (CNS), there is also a range of mechanical...
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...
Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are non-selective cation channels expressed in the brain and heart where they exert control over many diverse physiological properties. In the hippocampus, HCN channels are enriched in a dendritic gradient within CA1 pyramidal cells where they reduce dendritic integration and dampen neuronal excitability. HCN channels...
Decision making is an essential and indispensable element in everyday life. It is posited that parallel, distinct systems subserving deliberative, goal-directed control and automatic, habitual control underlie decision making. Computational accounts suggest that model-based and model-free learning strategies give rise to these two systems respectively. The model-based system is a...
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...
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...
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...
Slow-wave sleep (SWS) is important for overall health since it affects many physiological pathways from cardio-metabolic health to cognitive function. Sleep and autonomic nervous system (ANS) functioning are closely coupled at anatomical and physiological levels. Sleep-related changes in ANS function are likely the main pathway through which SWS affects many...
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...
Rhythmic oscillations in the brain are widespread. Extracellular recordings of local field potentials (LFPs) using methods ranging from microelectrodes to scalp electroencephalography (EEG) have demonstrated that oscillatory dynamics play a vital role in operations such as network synchronization, sensory tuning and information packaging. Empirical and computational evidence suggest that these...
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...
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...
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...
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...
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...
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 apolipoprotein E (APOE) E4 isoform is the strongest genetic risk factor for sporadic Alzheimer’s disease (AD). While APOE is predominantly expressed by astrocytes in the central nervous system, neuronal expression of APOE is of increasing interest in age-related cognitive impairment, neurological injury, and neurodegeneration. Here we show that endogenous...
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...
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...
Recent studies have begun to examine white matter connectivity aberrations in psychiatric populations, such as major depressive disorder. Several studies have found reduced white matter integrity (WMI) in depressed samples, though the location of this reduction is not clear. Incorporating symptom measures of depression severity and rumination may allow for...
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...
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...
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...
In mature neurons, postsynaptic NMDARs are segregated into two populations, synaptic and extrasynaptic NMDARs, which differ in localization, function, and associated intracellular cascades. These two pools are connected via lateral diffusion, and receptor exchange between them modulates synaptic NMDAR content (NMDAR-plasticity). Here, we identify the phosphorylation of the PDZ-ligand of...
Many species of rodents rely on the set of exquisitely sensitive facial vibrissae (whiskers) to guide rich behaviors in which other senses are inadequate. Although whiskers are, like all hairs, inert strands of keratin, they provide the animal with a rich landscape of tactile information which is used to guide...
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)...
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,...
Neurodegenerative diseases (NDs) commonly involve the accumulation and aggregation of neurotoxic proteins that impair and ultimately destroy specific neurons. Considerable evidence from human and animal studies indicates that many NDs show disrupted circadian and sleep as symptoms. Yet little is known about the molecular mechanisms by which genes cause NDs...
Dystonia is a movement disorder characterized by involuntary and repetitive co-contractions of the agonist and antagonist muscles. Dystonia 6 (DYT6) is an autosomal dominant dystonia caused by loss of function mutations in the zinc finger transcription factor THAP1. I have generated Thap1 knock-out mice with a view to understanding its...
Spinal cord injury (SCI) is a devastating injury, which can be caused by motor vehicle accidents, violence, and non-traumatic causes. These injuries can leave patients with lifelong paralysis, as well as incontinence and life threatening autonomic dysreflexia. There is currently no FDA approved treatment for SCI. Spinal injury disrupts the...
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...
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...