Stimulus generalization is a critical mechanism for facilitating behavioral flexibility. Generalization allows the brain to reduce computational demands that would otherwise be necessary to create unique representations for each and every encounter while allowing the ability to deal with the complexity of real-world situations. Stimulus generalization is a fundamental cognitive...
Herpes simplex virus (HSV) encephalitis (HSE) is the most common cause of sporadic fatal encephalitis, and despite targeted antiviral therapy, outcomes remain poor. While rare in adults, neonates are significantly more susceptible to severe HSV disease. Understanding both the host and viral factors that contribute to pathogenesis is critical to...
SCN2A encodes the NaV1.2 voltage-gated sodium channel, which is thought to contribute to the development of the central nervous system. Pathogenic variants in SCN2A have been associated with neurodevelopmental disorders (NDD), including developmental and epileptic encephalopathies (DEE), intellectual disability (ID), and autism spectrum disorder (ASD). These disorders represent a significant...
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...
The basal ganglia operate largely in closed parallel loops, including an associative circuit for goal-directed behavior originating from the dorsomedial striatum (DMS) and a somatosensory circuit important for habit formation originating from the dorsolateral striatum (DLS). An exception to this parallel circuit organization was proposed to explain how information is...
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...
Conversation is an important part of human life. Given globalization and the numerous languages around the world, it is increasingly likely that we will be communicating with others speaking in their second language (L2) rather than their first language (L1). In these situations, communication may require more effort. However, people...
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...
The retina does not act as a simple camera, rather visual information goes through multiple layers of processing before it reaches the brain. Retinal ganglion cells (RGCs) are the output neurons of the retina and process visual information in the retina and then project into the brain. There are over...
Cholinergic modulation of the brain cortex is critical for cognitive processes, and altered cholinergic modulation of the prefrontal cortex is emerging as an important mechanism of neuropathic pain. Despite the known sex differences in pain prevalence and perception, the precise nature of the mechanisms responsible for sexual dimorphism in chronic...
Understanding associative memory is fundamental for a variety of neurological and neurodegenerative diseases, however, a large proportion of this research has excluded female subjects due to unsubstantiated bias. By including intact females, ovariectomized females and males in the study of associative memory, clear sex differences in acquisition emerged. Female mice...
Chemokines, such as Stromal Derived Factor 1 (SDF-1 or CXCL12) and their G protein coupled receptors (GPCRs) are well known regulators of the development and functions of numerous tissues. CXCL12 has two receptors: CXCR4 and CXCR7 or atypical chemokine receptor 3 (ACKR3). CXCR7 has been described as an atypical “biased”...
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...
Breast cancer patients have reported nonspecific neurologic symptoms such as fatigue, depression, and cognitive concerns while undergoing adjuvant therapy. Few neuroimaging studies have examined hormone therapy, an adjuvant therapy, and more research is needed to determine possible neurologic and cognitive effects. Previous estrogen research has found alterations in gray matter...
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...
Interactions between working memory and long term memory systems are still not well understood, as the systems have long been thought to be mostly separate. An interesting intersection of these memory systems is domain-specific expertise, whereby individuals are able to show supra-span memory for information related to the area of...
Persons with spinal cord injuries can use state-of-the-art brain-computer interfaces to control robotic arms. Despite this high-tech solution, their movements are slow and imprecise, much like those made by individuals who have lost proprioception, the sense of body position and movement. Intracortical microstimulation (ICMS) used to reactivate neural circuits in...
The answer to the question “Why do we sleep?” lies in understanding the biological underpinnings of homeostatic drive to sleep. Wakefulness is correlated with numerous changes in brain activity, structure and gene/protein expression that re-normalize following sleep however which of these elements is sufficient to cause sleep drive and how...
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...
Aging is the greatest known risk factor for Alzheimer’s Disease (AD); however, the molecular mechanisms underlying aging and how it can initiate and or exacerbate AD, is still unknown. Epigenetic regulation has been widely accepted to play an essential role in aging or AD-related processes; however, whether dysregulations of histone...
The retina detects light, processes the visual signal, and sends a complex set of parallel information channels to the brain via a functionally diverse set of retinal ganglion cells types. This manuscript examines these retinal ganglion cell types, the visual features they encode, and the computational mechanisms leading to their...
Voltage-gated Na channels are expressed in all neurons, and are responsible for the upstroke of the action potential. They are part of a complex of proteins that includes pore-forming α subunits and auxiliary subunits that modify their trafficking, gating, and function. The modulation of Na channels by auxiliary subunits is...
Human olfactory function is important for a myriad of behaviors, including food seeking, social cognition, memory, emotional regulation, and detecting environmental threats. In animal models, particularly dense olfactory inputs have been shown to target orbitofrontal cortex (OFC), a region involved in multimodal sensory integration, reward coding, and flexibly guiding our...
The hippocampus has a well-established role in episodic memory and serves as a hub in a network of distributed brain regions (i.e., hippocampal-cortical network; HCN). Theta-band (4-8 Hz) neural activity recorded in the hippocampus have been associated with memory processing, and synchronized theta oscillations among the hippocampus and HCN regions...
Different features of the visual world are conveyed to the retino-recipient regions of the brain by more than 40 types of retinal ganglion cells (RGCS). Feature detection by RGCs depends on a combination of intrinsic and morphological properties where the interplay of excitatory and inhibitory inputs occurs through local retinal...
All animals purposefully navigate feature-rich environments: while exploring, in search of vital resources of food and water, finding mates, and patrolling and marking habitats. During these complex behaviors, continuous analogue input information from peripheral sensory organs guides discrete and digital sequential motor output; accordingly, each action is informed, modulated, or...
Research over the past several decades has revealed that memory reactivation in sleep contributes to the formation of long-lasting memories. Among the most recent developments in this field is the widespread use of the technique of targeted memory reactivation (TMR), which allows researchers to induce reactivation of specific memories during...
Neural stem and progenitor cell (NPC) fate specification is a crucial component of central nervous system development, and the myriad signaling pathways that guide it are poorly understood. In my thesis work, I aimed to elucidate signaling mechanisms of the bone morphogenetic protein family (BMP) and some of its targets...
Prions are self-perpetuating, alternative protein conformations associated with neurological diseases and normal cellular functions. Saccharomyces cerevisiae contains many endogenous prions – providing a powerful system to study prionization. Previously, the Li Lab demonstrated that Swi1, a component of the SWI/SNF chromatin-remodeling complex, can form the prion [SWI+]. A small region,...
The dentate gyrus is the first region for information processing within the classic hippocampal trisynaptic circuit, and this position makes it an important structure for the formation of associative memories. The dentate gyrus contains two major types of excitatory neurons: granule cells and mossy cells. While previous work has shown...
Melanopsin-expressing, intrinsically photosensitive retinal ganglion cells (ipRGCs) represent a class of non-canonical, ganglion cell photoreceptors. These cells influence a variety of visual behaviors including contrast sensitivity, circadian photoentrainment, sleep, and even mood. These wide-ranging behavioral influences are attributed to the multiple subtypes (M1-6) that comprise the ipRGC population, with different...
The cerebellar cortical system is an extensively studied circuit which is critical for motor learning. While multiple monoamines, such as norepinephrine and serotonin, modulate cerebellar cortical output, the mechanistic details of dopaminergic signaling in the cerebellum remain poorly understood. Additionally, neuronal cell types residing within the cerebellum remain relatively under-characterized....
Research on how sleep contributes to memory has blossomed in recent years. These studies have generally focused on whether or not sleep impacts various types of memory independently. An open question is whether sleep interactively influences different memory types. My research focuses on two types of memory—specificity and generalization. Whereas...
Autism spectrum disorder (ASD) and intellectual disability (ID) are two of the most highly prevalent neurodevelopmental disorders (NDDs), each affecting roughly 2% of the population. Despite the need for therapies, few exist due to a myriad of challenges, such as the complex underlying genetic etiology and historic inaccessibility of neural...
The exchange of information in the brain is accomplished through sequences of action potentials that result from the integration of local microcircuits. Unraveling the connectivity of the neurons that constitute these microcircuits and how they contribute to network activity is vital for understanding how information is relayed through the brain...
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...
We present two ways in which measures of information can be used for the design and analysis of neural networks in both the brain and the computer. In the brain, stimulus is often represented as a distributed pattern of activity in a network of neurons. The quality of such population...
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...
Vertebrate brains evolved to facilitate a diverse array of behaviors and internal cognitive processes. Theories of neural function have proposed that neural computation is organized within populations or ensembles of neurons. Here, we identify ensembles of neurons in the striatum, the main input nucleus of the basal ganglia, in which...
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...
Temperature affects all biological processes, from the rate of cellular growth and metabolism to the stability of proteins that make up the machinery of life itself. Thus, all organisms must have the capacity to detect and respond to external temperature. Thermosensation endows animals with the ability to sense and respond...
Coordinated movement relies on the precise and controlled activation of populations of motor units, which convert the commands of the nervous system into muscle forces. Motor unit firing patterns are often nonlinear and generated through the response to a combination of ionotropic excitatory and inhibitory commands, as well as metabotropic...
Glioblastoma multiforme (GBM) is the most prevalent primary central nervous system tumor, characterized by resistance to therapeutic intervention, inevitable recurrence, and ultimately patient death. The dismal prognosis is due in part to underlying molecular factors that promote an intratumoral cellular state heterogeneity and protect tumor cells from cell death pathways....
Human olfactory function is important for a myriad of behaviors, including food seeking, social cognition, memory, emotional regulation, and detecting environmental threats. In animal models, particularly dense olfactory inputs have been shown to target orbitofrontal cortex (OFC), a region involved in multimodal sensory integration, reward coding, and flexibly guiding our...
Processing of sensory information in the brain is a pervasive and fundamental phenomenon across animal species and is involved in both "hard-wired" innate responses as well as learned and adaptive behaviors. Here, I show that the avoidance of hot temperature, a simple innate behavior, contains unexpected plasticity and complex processing...
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...
Decisions in naturalistic environments usually feature delayed and uncertain outcomes that can only be reached after a sequence of actions are performed. For example, canonical stalking and pursuit strategies used by terrestrial predators often involve stages of concealment, pauses where the predator remains motionless, and high speed chase sequences. The...
Protein homeostasis, or proteostasis, is essential for preserving all cellular functions and involves a balance of protein synthesis, folding, trafficking, and degradation. A collapse in proteostasis is a common feature of many neurodegenerative disorders that are characterized by the accumulation of insoluble protein aggregates in the brain. Parkinson’s disease (PD)...