Past Research Topics

The Development Basis of Dopaminergic Neuron Diversity
Parkinson’s disease (PD) is characterized by a substantial depletion of a subset of midbrain dopamine neurons (mDA), the loss of which accounts for most motor deficits observed in this disease. Recent studies have revealed that specific subsets of mDA are lost in PD. This selective mDA neuron susceptibility in PD highlights heterogeneity of the mDA system. Thus, replacing specific subtypes of mDA, as opposed to generic mDA, has been highlighted as an important goal of stem cell–based therapies for PD.

The goal of this study is to understand how different mDA subtypes are generated. Experiments will be conducted that define how in the embryo, midbrain progenitor cells are directed by specific gene/gene combinations to yield distinct mDA subtypes. To do so, specific progenitor cell populations will be indelibly labeled using conditional genetic techniques, thus determining what subtypes of mDA are produced from distinct progenitor pools. These experiments will define the developmental basis for mDA diversity. Understanding the developmental cascades underlying mDA diversity will be critical for generating stem cell–derived therapies or models of PD.

Optogenetic Analysis of Mammalian Olfactory Circuits
Understanding how nerve cells are connected to form functional circuits is essential to understanding how the brain works. Traditional anatomical techniques can reveal the structure of neuronal circuits. However, determining which nerve cells actually communicate with one another in a complex circuit is more challenging. Recent advances in genetics have ushered in a new age of functional circuit mapping. Specific neuron population in the intact mouse brain can be genetically “tagged” with a light-activated channel, allowing the selective activation of spatially defined subsets of neurons with light.

Using this photostimulation-based approach, the goal of this research is to map the strengths of local circuit connections in the olfactory bulb, a part of the brain that processes sensory information about smell. The olfactory system will be targeted because it is well characterized, genetically tractable, and functionally important to the animal. The research described here will address fundamental questions about sensory processing that were previously not possible to address using traditional techniques. Future work will focus on how the activation of specific circuits using light elicits or influences odor perception. The “optogenetic” approach described here can also be further utilized to study other parts of the mammalian brain.

Organization and Development of Motor Maps in the Mouse Superior Colliculus
The mammalian superior colliculus (SC) is a subcortical structure that integrates visual and other sensory information and controls eye and head movements to orient the animal toward novel sensory stimuli. The SC is divided into superficial and deep layers corresponding to a sensory representation of the external environment and a motor representation responsible for the control of orienting responses within that environment. Much attention has been devoted to development of the sensory representation in the superficial layers, which contain an orderly topographic map of visual space. In contrast, development of the motor map in the deep layers has not been studied. In fact, little is known about the development of motor representations anywhere in the central nervous system.

In this study, the hypothesis that the development of the SC motor map is patterned after the overlying sensory map will be tested. The experiments will provide the first systematic mapping of the deep layers of the mouse SC. This will be followed by examination of the motor representations in mutant mice shown to have disrupted visual maps in the superficial layers. The hypothesis predicts that the organization of the motor map in these mice will closely parallel the disrupted visual map in these mice.

Gene Therapy for Treatment of Epilepsy
Epilepsy is a disease of abnormally increased brain excitability that leads to seizures. Some patients with epilepsy continue to have debilitating seizures despite trying all of the available antiseizure medications and even undergoing brain surgery to try to remove areas of the brain causing seizures. Brain excitability is controlled in large part by proteins called ion channels. The h channel family of ion channels consists of four different genes, HCN1-4, and has been implicated in epilepsy in animals and humans.

This project will examine whether using viruses to produce HCN2 in abnormal areas of the epileptic brain can stop seizures. First, a virus will be engineered and delivered to the brains of epileptic mice to prove that it makes HCN2 protein in the proper brain cells. Then, it will be determined if expression of HCN2 by the virus stops seizures. These experiments aim to develop and test techniques for viral gene therapy in an animal model of epilepsy with the ultimate goal of finding new treatments to help patients with intractable epilepsy.

In Vivo Analysis of the Role of FMRP in Dendrite Maturation and Plasticity in the Somatosensory Cortex
Fragile X syndrome is the most common form of human mental retardation and the single largest known cause of autism. One prominent manifestation of the disease is an alteration in sensory processing that results in tactile hypersensitivity in fragile X patients.

This study seeks to define the impairments in dendritic maturation and plasticity in the sensory cortex of a fragile X mouse model. The results will help determine the role that the fragile X mental retardation protein plays in the development and plasticity of neurons that underlie sensory processing.

INSM1 in Terminal Neurogenic Proliferation
The size and shape of every part of the brain are determined by how much the neuronal progenitor cells divide during embryogenesis. In nematodes, a gene has been identified that is expressed at the end of neuronal proliferation and delimits the number of neurons produced. In mammals, a homologous gene is similarly expressed at the end of neuronal proliferation.

In this project, this gene will be mutated in mice to determine whether it regulates neuronal proliferation and brain size.

The Role of AMPA Receptor (GluR2) Trafficking in Cerebellar Plasticity in Adult Mice: An Imaging Study
A hallmark feature of our brains is their enormous capacity for information storage and learning. In neuronal circuits, information is stored through long-term changes in the efficacy and gain of synaptic communication, as in long-term potentiation and long-term depression. But what mediates the changes in synaptic gain? Are they due to changes in response properties of individual transmitter receptors, or the changes in the number and density of receptors at the synapses? Recent studies using neuronal cultures suggest that trafficking of receptors in and out of the synaptic membrane regulates synaptic gain. A caveat of these experiments is that cultures keep neurons “locked” in an early developmental stage.

Using a combination of patch-clamp recordings and imaging techniques, the goal of this research is to examine whether glutamate receptor trafficking also plays a key role in synaptic memory storage in the adult brain.

The Role of Seizure-like Activity Driving the Progression of Alzheimer’s Disease
Alzheimer’s disease (AD) is a progressive brain disorder characterized by the formation of two pathological features, plaques and tangles. Research has shown that this abnormal pathology of the brain develops in a very characteristic pattern over time. A key to understanding AD is to understand how this progression occurs. Our working model is that brain cells become “hyperactive,” similar to the activity measured during very mild seizures; this abnormal activity then causes the characteristic AD pathology to develop in this area. Moreover, this hyperactivity travels to other regions by specific connections in the brain, causing these “downstream” areas to also become excitable and initiating pathological changes in these new areas. This in turn affects other areas, causing a specific cascade of hyperexcitability and subsequent AD pathology; this hyperactivity drives the progressive pathology in the brain. Studies have reported seizure-like activity in AD patients and animal models of AD; in fact, recent studies in animal models of AD have shown a type of “silent seizure,” suggesting there is an undetected hyperactivity in the AD brain.

In this project, sensitive monitoring devices will be placed in a mouse model of AD to determine if the sequence of the developing pathology is preceded by hyperactivity. To further understand this problem, drugs that block this hyperactivity, including antiseizure medications, will be administered, testing the drug at different time periods. This will help in understanding if hyperactivity is involved, and also if interrupting hyperactivity at a specific time may block “downstream” areas from developing AD pathology. A better understanding of this relationship is warranted and may be extremely valuable in identifying mechanisms responsible for this devastating disease. Most important, this understanding may suggest that drugs blocking or reducing hyperactivity in the brain may be able to stop the initiation or progression of the disease; currently, we are only treating the symptoms. The potential of this research is that antiepileptic drugs, which block neuronal hyperexcitability, may be useful in treating AD. Because these drugs are currently used to treat epilepsy, they could be rapidly transitioned to the treatment of AD.

Functional Neurobiology of Harsh Maternal Parenting
Harsh maternal parenting in childhood is a robust risk factor for many mental disorders and chronic diseases in offspring. Furthermore, animal studies indicate that atypical early mothering causes lasting changes in gene expression that disrupt neural and endocrine systems. Thus, programs that reduce early harsh parenting could have great public health benefits, just as programs to reduce smoking reduced lung cancer. Unfortunately, it is difficult to help mothers to reduce their harsh parenting. Even when abusive mothers are motivated to change, it is difficult for them to do so.

Understanding harsh parenting at neurobiological levels may lead to breakthroughs in treating harsh parenting. The hypothesis for this research is that harsh mothers will exhibit both greater activation of brain systems involved in negative emotion and less coordinated activation of cortical control systems when viewing images of child misbehavior. In addition, genes known to influence animal maternal behavior may be associated with maternal neural responses to child stimuli.

Deciphering the Roles of DISC1 Isoforms in Embryonic Brain Development
Schizophrenia is a debilitating developmental illness characterized by multiple symptoms including hallucinations, delusions, and social withdrawal. Schizophrenia is an inherited disorder, in that, if a family member is affected by schizophrenia, the other members have an increased risk of developing the disease as well. Multiple schizophrenia susceptibility genes have been identified, including DISC1 (Disrupted in Schizophrenia 1). DISC1 is a susceptibility gene not only for schizophrenia, but also for bipolar affective disorder, autism, and Asperger syndrome. There are multiple forms of DISC1 expressed in the developing brain.

This research will examine the function of these multiple DISC1 variants during development. It may be that disrupting the function of a specific DISC1 variant determines whether an individual has increased susceptibility to schizophrenia, bipolar affective disorder, or autism. In order to develop new therapeutics, a better understanding of the genetic basis of the disease is critical.

Epigenetics in Spinocerebellar Ataxia
Increased understanding of events that lead to chronic degenerative diseases that affect the brain is needed. Currently, studies focus on a genetic disease that leads to cerebellar pathology called spinocerebellar ataxia type 1. This disease is caused by a genetic mutation that leads to an expansion of glutamines (an amino acid) in the protein encoded by this gene. One leading hypothesis is that the diseased protein leads to changes in gene expression that cause deleterious events.

The goal of this research is to identify the mechanisms underlying these changes in gene expression so as to lead to future avenues of therapy.

Investigation of Molecular and Genetic Controls Over Cell-Type–Specific Vulnerability of CSMN in ALS
Investigation of molecular and genetic controls over survival and degeneration of subtype-specific neuron populations in relation to disease is critically important. Neurodegenerative diseases stem from progressive and cell-type–specific degeneration of a defined neuron population in the central nervous system. Today, the cellular and molecular mechanisms of cell-type–specific degeneration are poorly understood. It is not clear why, in the complex structure of the brain, only specific neuron populations undergo cell death. This limited understanding of cell-type–specificity hinders the identification of approaches for cure and restricts the ability to detect early the vulnerability of a defined neuron population. We are realizing that the cortex cannot be defined only by layers, but must also be defined by subtype-specific neuron populations that are molecularly related to each other. The genetic makeup of different projection neurons and interneurons are beginning to emerge. Using pure populations of subtype-specific neurons, the molecular controls over their birth and specification, as well as their neuronal maturation and axon outgrowth, are identified.

Corticospinal motor neurons (CSMN) reside in layer V of the motor cortex, and together with spinal motor neurons, progressively degenerate in amyotrophic lateral sclerosis (ALS). CSMN degeneration is also observed in primary lateral sclerosis and hereditary spastic paraplegia. In addition, CSMN degeneration contributes to the long-term paralysis in spinal cord injury. Callosal projection neurons (CPN) are born together with CSMN and reside together with CSMN in layer V, but they are not affected in such diseases. Subtype-specific neurons share a common biology, a common molecular structure, and, during times of disease, a common destiny. This common, yet undefined, molecular signature could be one major reason why a defined neuron population is more vulnerable in a disease.

Symptoms of motor neuron degeneration develop late in disease progression; however, cell death starts much earlier. This indicates the presence of an intrinsic molecular mechanism that makes these neurons more vulnerable to disease. Understanding the molecular and genetic controls over CSMN-specific vulnerability can offer a tool for identifying the basis of cell-type–specific degeneration of this clinically relevant neuron population. Investigation of pure populations of CSMN isolated from well-defined animal models of diseases at two critical time points, and using CPN as a control neuron population, will allow identification of key genes, gene clusters, or molecular pathways that may reflect in human disease pathology.

These findings will help to identify novel molecular markers that can be used for early diagnosis, and may enhance development of effective therapies in the future.

Chronic Stress Causes Pathology of K⁺ Channels in Amygdala Neurons
Prolonged stress causes long-term harmful effects, including persistent emotional disruptions, and induces the emergence of clinical depression. The amygdala, a key brain region in emotion, is a target of the effects of stress, and displays abnormalities in depression. However, it is unknown how stress alters the activity of the amygdala.

This project will examine the impact of stress on emotion by determining whether stress leads to abnormally active amygdalae, and the biological substrates of this disruption. Understanding the cellular targets of stress in the amygdala can lead to novel preventive strategies for depression.

A Brain-Machine Interface Based on Movement-Related Potentials From Epidural vs Subdural Signals
More than 600,000 people in the US have severely impaired motor function from disorders including amyotrophic lateral sclerosis, brainstem stroke, and spinal cord injury. The cost of caring for these patients runs into the billions of dollars. Brain-machine interfaces (BMIs) have the potential to free patients from the shackles of these paralyzing disorders by decoding signals recorded from the brain into commands to control the movements of a computer cursor, a prosthetic limb, or even a person’s own limb. These signals have been recorded from different levels of the brain, using noninvasive electrodes on the scalp to electrodes placed on top of the brain or even inside the brain itself. In general, there is a trade-off between invasiveness and the signal quality. Recently, several research groups have had success at allowing nonparalyzed patients, already undergoing brain surgery for different reasons, to use intermediate-level (subdural) signals to control a cursor movement in two dimensions.

This research will investigate a less invasive (epidural) level of signal to decode not only cursor movements, but also the movements of the fingers and muscle activity while the patient performs one of several grasps. If individual finger movements—or even one of several grasps—can be decoded, these signals may be able to control a device that would electrically stimulate a paralyzed person’s arm muscles to restore these hand and finger movements. Also, the mathematical techniques used to decode these signals rely on brain signals that are related to the way people normally move. This is different from the BMIs that currently are used with subdural signals.

Synaptic Circuit Organization of the Rubro-olivary System
In mammals, the control of movement relies on networks of neurons in many different brain regions. A major pathway linking different motor circuits is in the brainstem, linking “upstream” neurons in the red nucleus (RN) to “downstream” neurons in the inferior olive (IO) nucleus. The IO neurons project onward to the cerebellum, which projects back to the RN to form a loop, and the RN also receives signals from the cerebral cortex. Pathology of rubro-olivary (RN-to-IO) connectivity causes profound loss of motor control, and degeneration of IO neurons. The rubro-olivary projection is clearly of major importance for motor control, but, remarkably, the actual function of this projection remains highly controversial, especially because of an almost complete lack of data about the connectivity and synaptic physiology underlying this projection.

This project will use a novel combination of cutting-edge circuit analysis tools to elucidate the synaptic organization of the rubro-olivary pathway, as a first step toward developing paradigms for analyzing subcortical motor circuits in general.