In everyday conversation, individuals actively process speech in order to comprehend and respond in real-time. As a word unfolds, listeners activate possible lexical candidates and actively determine the target word as they receive more information, a process referred to as incremental processing. This process requires knowledge of one’s native spoken...
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...
In the adult hippocampus of many mammalian species, populations of newborn dentate granule cells (DGCs) are continuously generated and undergo subsequent activity-dependent neuronal maturation and incorporation into the preexisting hippocampal circuitry. Increasing evidence has demonstrated that these young adult-born DGCs (abDGCs) participate in numerous cognitive and affective processes such as...
My research at northwestern with Dr. Christina Zelano focused on the human amygdala subnucleithat receive monosynaptic input from the olfactory bulb. Surprisingly little is known
about these brain regions, including their potential roles in olfactory and nonolfactory
processing. During my PhD, I completed three projects aimed at furthering our understanding...
Social engagement, or shared attention between a child and caregiver, is a critical process for language and social development. Although previous EEG studies have investigated child social processing in closely controlled, experimental studies, no study has examined the interactive, reciprocal process of naturalistic social engagement. In my first paper, we...
Parkinson’s disease (PD) is the second most common neurodegenerative disorder, causing devastating disabilities in both motor and non-motor domains following the degeneration of dopamine (DA) producing neurons of the substantia nigra pars compacta (SNc). Current treatments are highly limited in efficacy, and no established treatments currently exist to alter disease...
Glioblastoma (GBM) is the most common aggressive primary malignant brain tumorin adults with a median age of onset of 65 years of age. Although advanced age is often associated with worse GBM patient survival, the predominant source(s) of maladaptive aging
effects remains to be established. Here we studied intra-tumoral and...
Stroke is the leading cause of permanent adult disability. Subcortical unilateral (hemiparetic) stroke affecting the internal capsule or basal ganglia is the most common of all strokes and usually results in hemiparesis of the contralateral arm and leg. About 80% of the individuals with a moderate to severe hemiparetic stroke...
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...
Leptin, a peptide mainly secreted in proportion to adipose tissue mass, increases energy expenditure with a parallel increase in breathing. The existence of a leptin-mediated neural circuit linking breathing to metabolism has been speculated, yet the precise central mechanisms were unknown. In my thesis, I show that optogenetic activation of...
Electrical spinal cord stimulation is an emerging treatment for spinal cord injury that can improve walking and bladder control, among many other functions. While the anatomical location of the motor pools for muscles involved in locomotion in the lumbosacral cord has been identified, the map of the functional output of...
Dynamic decision-making is a complex process that relies on our ability to generate, evaluate and implement a variety of strategies. Understanding how people navigate this process is a difficult problem that requires a wide range of methodologies. This study details a combination of behavioral experiments, computational modeling, and neuroimaging that...
Genetic studies have found variants in the protein-degrading autophagy-lysosomal pathway (ALP) to be among the most common risk factors for developing Parkinson’s disease (PD). Macroautophagy (MA) is the arm of this pathway which delivers cytosolic components to lysosomes for degradation and is essential for neuronal health. The defining pathological protein...
The current view in neuroscience holds that the brain, together with its sensory and motor structures and the environment, form a closed-loop system – a sensorimotor loop – in which the brain receives information from the environment and converts it into a motor response while simultaneously making predictions about future...
Anxiety and depression are highly prevalent, recurrent, and major public health problems. Decades of research has uncovered associations between symptom dimensions of anxiety and depression and abnormal neural activation across executive control-, threat-, and reward-related networks. Recent studies have developed a hierarchical symptom structure of anxiety and depression termed the...
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...
Each neuron in the primary motor cortex (M1) is like a musician in an orchestra, contributing to a larger harmony under the constraint of a “neural manifold”—a geometric score describing the correlated signals produced by the neural musicians that drive movement. Despite the widespread recognition of the importance of M1...
Chronic stress is a significant risk factor for the development of numerous psychiatric disorders, including major depressive disorder (MDD). Individuals with MDD exhibit impairments in reward processing and decreased motivation to engage in previously-rewarding activities. Importantly, there is a large sex disparity in MDD diagnosis, such that it affects nearly...
Movement and sensing fundamentally works in a synergistic manner. Animal's sensory organs --- be they independently movable like eyes or requiring whole body movement as in the case of electroreceptors --- are actively manipulated throughout stimulus-driven active sensing behaviors. Though these sensing-related motions have been individually reported and analyzed across...
Affect represents a major domain of human consciousness, consisting of a complex group of psychophysiological processes to drive human behavior. Many genetic and environmental factors may cause dysregulation of affective states, resulting in disorders that severely disrupt normal cognitive function and diminish the quality of life. Transitions among affective states...
We present a biophysical model of GCaMP6f calcium fluorescence in CA1 pyramidal neuron dendrites based upon results from imaging and electrophysiology experiments. This work was completed using experimental results from the laboratory of Professor Daniel Dombeck, Department of Neurobiology. Constraining the model to reproduce different objectives --- from in-vitro and...
As of 2020, there are currently 5.8 million people in the United States suffering from Alzheimer’s Disease (AD), a debilitating and progressive neurodegenerative disorder. Of these nearly six million people, two-thirds are women. While it has been suggested that women’s longer lifespan accounts for this disparity, the overall lifetime risk...
Mitochondrial complex I is the primary entry point for electrons into the mitochondrial electron transport chain that is composed of 45 individual protein subunits that are encoded in both the nuclear and mitochondrial genomes. Mitochondrial complex I sits at an important nexus in the essential bioenergetic, biosynthetic, and signaling functions...
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...
Voltage-gated potassium (KV) currents play a crucial role in shaping and controlling the firing patterns that serve as the fundamental basis for the differential signal processing from the ear to the auditory cortex, with distinct firing patterns observed with high- and low-frequency phenotypes. This is an interesting phenomenon, in the...
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...
In memory overgeneralization, details from negatively-valenced episodic memories become excessively generalized to unrelated neutral situations. This is a key cognitive distortion associated with major depressive disorder (MDD), generalized anxiety disorder (GAD), and post-traumatic stress disorder (PTSD). Stress promotes memory generalization, and this process likely relies on stress-induced changes in dorsal...
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...
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by motor neuron (MN) degeneration and resulting in progressive paralysis and death. ALS is genetically heterogeneous, disease pathophysiology is not completely understood, and there are no effective drug therapies. To develop broadly applicable therapeutics, we examine disease mechanisms in the...
Simple sensorimotor tasks, such as lifting a cup or balancing a tray, requires not only controlled motor output, but also the ability to accurately perceive sensory information. After a hemiparetic stroke, individuals often experience sensory deficits in addition to motor impairments. However, research on the extent of changes in sensory...
Brain network organization, the emergence of cognition, and the accumulation of neurodegenerative pathology are interwoven concepts frequently studied under the umbrella of behavioral neurology, neuropsychiatry, neuropsychology, and neuropathology. One approach to studying the organization of cognitive processes is to study those with selective deficits in such networks. To understand how...
Considerable progress has been made in characterizing the neural circuits that underlie stress, fear, feeding, and pain. However, little is known about how they affect each other. Stress bidirectionally regulates feeding, either increases (e.g., stress-induced binge eating) or decreases (e.g., stress-induced anorexia), depending on the types of stressors, duration of...
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...
The interaction of amyloid-β (Aβ) with endogenous metal ions is thought to play a role in the pathogenesis of Alzheimer’s disease (AD). However, limited tools exist to study and modulate Aβ-metal binding. The Meade lab has developed cobalt(III) Schiff base (Co(III)-sb) complexes as protein inhibitors that competitively displace metals from...
Nearly all animals exhibit behaviors that can be classified as sleep. The distinctly disadvantageous nature of the asleep state, evolutionarily speaking, accentuates its role as a critical physiological process, yet chronic inadequate sleep is prevalent in today’s society. Among the multitude of health problems that have been linked to chronic...
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...
Movement is achieved by combining synaptic inputs from various sources and activating motor unit populations. Motor units are the quantal elements of motor control which act as a neuromechanical transducer that converts sensory inputs into motor output. Because of the tight neuromuscular junctions between motoneuron axon terminals and a large...
Basal ganglia are a highly interconnected group of nuclei involved in motor control. The external globus pallidus (GPe) is a critical node within the basal ganglia circuit. While the prevailing basal ganglia circuit model assumes the GPe as merely a relay, phasic changes in the activity of GPe neurons during...
Dopamine neurons are characterized by their response to unexpected rewards, but some also fire during movement and in response to aversive stimuli. Dopamine neuron diversity has also been observed based on their genetic expression profiles, suggesting that different functions might map onto such genetic subtypes. However, this has not been...
The basal ganglia are a remarkably complicated and interconnected tangle of subcortical nuclei whose exact function and composition are hotly debated to this day. What is plainly obvious, however, is that loss of dopaminergic modulation in the basal ganglia, as is the case in Parkinson’s disease (PD) following the progressive...
Mitochondria-lysosome contacts are recently identified sites for mediating crosstalk between both organelles, but their role in normal and diseased human neurons remains unknown. We used super-resolution and live-cell microscopy in human iPSC-derived neurons to demonstrate that mitochondria-lysosome contacts can dynamically form in the soma, axons, and dendrites of human neurons,...
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...
Approximately 80-90% of individuals with Parkinson’s disease (PD) develop motor speech impairments, predominantly in the form of voice dysfunction. It is known that the motor symptoms of PD arise from degeneration of the dopamine producing neurons in the substantia nigra and dysregulation of basal ganglia motor pathways. It is also...
Voltage-gated potassium (KV) currents play a crucial role in shaping and controlling the firing patterns that serve as the fundamental basis for the differential signal processing from the ear to the auditory cortex, with distinct firing patterns observed with high- and low-frequency phenotypes. This is an interesting phenomenon, in the...
Background: The way in which one perceives their visual world (i.e., bottom-up visual perception) and what one pays attention to in their surroundings (i.e., top-down attention), are critical to uncovering underlying thoughts and cognitions, and impact how one operates in the social world. Individuals with autism spectrum disorder (ASD), a...
The mammalian retina contains three classes of photoreceptors: rods, cones and the recently discovered intrinsically photosensitive retinal ganglion cells (ipRGCs). ipRGCs express the photopigment melanopsin and were initially thought to be a homogeneous population of cells that drive subconscious visual behaviors such as circadian photoentrainment and pupil constriction. However, recent...
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...
A one-time, unilateral injury to the developing brain can interrupt the typical process of development and result in motor impairments that evolve over the course of the whole life-span. The timing of injury relative to neural development has implications for the continued refinement of the nervous system and the descending...