DEPARTMENT OF NEUROBIOLOGY
EXAMPLES FOR THE NON-SPECIALIST OF RESEARCH CONDUCTED IN
LABORATORIES OF PRIMARY, SPLIT, AND SECONDARY FACULTY

Bok, Dean
Buonomano, Dean
Cooper, Edwin
Edgerton, V. Reggie
Engel, Jerome
Glanzman, David

Dean Bok, Ph.D.
Professor of Neurobiology
Dolly Green Professor of Ophthalmology

Dr. Bok's research interests involve the retina, an extension of the brain that lines the inner surface of the eyeball. Light enters the eye through the cornea, pupil and lens, and the image that it carries is focused on the photoreceptor cells of the retina. Two classes of photoreceptor cells initiate the visual experience, the rods, which are used in dim light and the cones, which function in brighter light and provide color vision.

Dr. Bok studies the normal processes that keep photoreceptor cells in good health and the mechanisms that cause them to die in retinal disease. Unfortunately, as a consequence of genetic factors, aging and environmental factors, photoreceptor cells undergo damage and either become impaired or die. This is the case with inherited diseases such as retinitis pigmentosa, macular degeneration and Usher syndromes. In the latter example, both vision and hearing are impaired or lost.

The research efforts in Dr. Bok's laboratory are focused on understanding why and how photoreceptor cells of the retina die because of gene mutations. His primary research tool is naturally occurring or genetically engineered animal models of human disease. Utilizing these animal models, Dr. Bok and his collaborators are testing various methods for replacement or substitution of defective genes in order to rescue photoreceptors cells from degeneration.

Edwin Cooper, Ph.D., Sc.D.
Professor of Neurobiology
Laboratory of Comparative Neuroimmunology

Development for Neuroscience

The proper functioning of the human body from birth through aging is monitored by our three great regulatory systems: nervous, endocrine and immune. Each of these systems is composed of cells, tissues, and organs. And each system's cells make (synthesize?) and secrete certain molecules that help to maintain functional integrity. It is interesting that each of these systems acts independently of each other; however, to maintain the proper balance, there is enormous cooperation, sharing and collaboration among the three systems. For example, cells of the immune system contain on their surfaces tiny identification badges or receptors that can be recognized by cells of the nervous, immune and endocrine systems. Once recognized, the cell wearing the badge receives a lot of signals that are transmitted into the cells internal machinery, telling it what to do. This capacity to interact in a highly orchestrated manner with minimal mistakes or flaws keeps us healthy and free of diseases such as cancer or neuro-degenerative diseases. In other words a proper balance of the internal environment of the body is maintained and under optimal conditions, which allows for proper interaction with the external environment.

Thus, our bodies can be visualized as a giant network with many communicating connections—sometimes hard wired, that is sometimes inflexible, but other times this intricate network is highly flexible. This enables us to accommodate to changes in order to maintain the internal environments of our bodies and the external environments in which we live. For the immune system there is strong evidence that without its properly balanced function, by means of cells that police or survey the internal body, we become prone to the development of cancer. And we have evolved a group of cells called natural killer cells (NK cells) that have been assigned this function to act as police, cells whose function is immunosurveillance, of the internal landscape for potential aberrations in cell structure and function. When this occurs, the body's NK cells are rapidly deployed to kill or lyse the potentially menacing cell that could become cancerous. In some instances, we can become vulnerable to developing diseases as a result of improper handling of toxic environmental stimuli that, too, can lead to the development of certain diseases.

It is of great interest to determine how these nervous, immune and endocrine systems develop during embryonic stages when we were just a fetus. In addition, it is equally fascinating to understand where the cells, tissues, organs and molecules of these three systems first appear independently during the evolution of all animals including humans. It is of enormous importance for the treatment of diseases to know where there was co-evolution or development of these components. Understanding this co-development sheds light on how certain treatment strategies can be defined and later implemented in animal models and eventually in clinical trials.

Humans as mammals share their backbones with other vertebrates (fish, amphibians, reptiles, birds and mammals). However, there are numerous other animals without backbones, the invertebrates, some of which are pests (flies, mosquitoes), some are sources of food (oysters, shrimp) and others are beneficial for the environment (earthworms). These animals constitute a significantly larger number of living creatures in the biosphere. Aside from their economic importance, invertebrates are outstanding examples of inexpensive, non-controversial animal models from which we can learn more about what ails humans and how to cure these diseases. We can search for models of diseases in the nervous, immune and endocrine systems and find numerous examples of how these models apply quite specifically to human conditions. After all, the invertebrates evolved on the earth millions of years ago and yet they survive. Thus their survival strategies are worth analyzing and understanding for the benefit of human kind. Invertebrates have potent antimicrobial peptides and proteins and, in general, do not develop cancer. Is this due to their immune system's capacity to rapidly eliminate potentially cancerous cells more efficiently than the human immune system? Can their molecules be utilized in the development of potent new wave antibiotics since those that are commercially developed are often ineffective in hospitals against certain vicious viruses, bacteria and fungi?

We will be identifying molecules that may be harnessed in an attempt to decipher what can be effective in complementary and alternative approaches. By means of a new project, establishing a new journal, ( Evidence Based Complementary and Alternative Medicine [eCAM] ) to be published by Oxford University Press, we will have the usual scientific vehicle for discovery. A final point to consider when looking at the value of invertebrate models or vertebrate models like the zebra fish is the problem of maintenance and cost in the ever mounting federal expense of maintaining animal models usually mice and other mammals. After all, if we can arrive at understanding what ails us and make predictions about cures by using thousands of inexpensive fruit flies or round worms or zebra fish, then such an approach is worth the effort of the scientific community.

V. Reggie Edgerton, Ph.D.
Professor of Physiological Sciences and Neurobiology

The Neuromuscular Research Laboratory is focused on understanding how the nervous system controls movement. Their objective is to understand and formalize some generalized principles for motor control. More specifically, their studies are designed to further understand how the spinal cord controls posture and locomotion. The principal experimental model being used to accomplish this goal is spinal cord injury, and in most cases this involves complete spinal cord injury. However, other experimental paradigms used to study the plasticity of the neuromuscular system in the absence of weight-bearing are spaceflight, suspension of the legs to prevent weight-bearing as well as normal in vivo neuromuscular performance in the 1 g environment. The highest priority within this laboratory is to understand the plasticity potential of the spinal cord and musculature with respect to the ability to recover functional posture and locomotion following spinal cord injury and other neuromotor disorders. These problems are being addressed at the in vivo level using mice, rats, nonhuman primates and in humans. A primary focus is to elucidate the molecular, cellular and system level mechanisms by which the spinal cord can learn specific motor tasks such as stepping and standing following injury. A second focus is to define the physiological-biochemical events in motor neurons and muscle fibers, controlling expression of genes which define muscle fiber phenotypes. In combination with interventions that include activity-dependent mechanisms such as step or stand training, they are examining the efficacy of combining activity-dependent interventions with nerve growth factor treatment, implantation of engineered cells, implantation of olfactory ensheathing cells, radiation, spinal cord stimulation, muscle stimulation and implantation of axons. They are developing robotics devices to analyze movement and to train spinal cord injured animals to relearn how to stand or to step.

In their efforts to reach their highest priority as well as to understand fundamental principles of the neural control of posture and locomotion, they are participating in a number of projects. Their collaborators include investigators within UCLA as well as scientists from other U.S. and international universities. One of their principal collaborative efforts consists of studies organized within the Christopher Reeve Paralysis Foundation Consortium. Another collaborative effort is in the form of a Program Project Grant funded by NINDS. Currently these and other individual projects are funded by NIH, CRPF, NASA and the California Roman Reed Spinal Cord Injuries Fund. Some of these projects are outlined below.

Major Accomplishments:

They demonstrated that:

1) After complete spinal cord transection, animals, including humans, can learn to step if they are trained to step. They also demonstrated that one can learn to stand if they are trained to stand. These experiments also demonstrated that the spinal cord learns what it is trained to perform. If it is trained to stand, it will become very good at standing but not necessarily stepping.

2) The spinal cord is smart. This means that the spinal cord can receive sensory information from the legs and make smart decisions about how to use that sensory information. In other words, the sensory information is not treated simply as a stereotypical reflex but as a piece of information that provides sufficient meaning for the spinal cord to make appropriate decisions for helping to maintain a standing posture or to continue stepping without altering.

3) Following spinal cord injury there are biochemical changes which favor inhibition of activity rather than activation.

4) The muscle mass following spinal cord injury can be maintained with extremely minimal levels of electrical stimulation, thus minimizing the negative impact of muscle atrophy following spinal cord injury.

5) Training an animal following spinal cord injury will reduce this inhibition so that the spinal cord will become more excitable when it is provided the appropriate sensory information related to weight-bearing stepping and standing.

6) There are several ways in which they can modify the biochemistry of the spinal cord using pharmacological interventions. For example, they can administer pharmacological agents which will reduce inhibition and enable animals to step with full weight support within minutes after administration, even in animals that were completely unable to step prior to the administration of the pharmacological agent.

7) State-of-the-art robotic devices can be used to train mice and rats to step. These devices may prove to be extremely viable in the research environment in which efforts are being made to establish interventions that can lead to major improvement in function following spinal cord injury. These devices will also be helpful in developing techniques which can be used in training human subjects using robotic devices.

Jerome Engel, M.D., Ph.D.
Professor of Neurology and Neurobiology

Epilepsy is a common serious disorder that is frequently misunderstood and/or ignored by neuroscientists. One in ten people suffer at least one epileptic seizure during a normal lifespan, and one-third of these will develop a chronic epileptic condition. The World Health Organization has determined that epilepsy accounts for 1% of the global burden of disease, equivalent to lung cancer in men and to breast cancer in women. Among disorders of the brain, epilepsy ranks with depression, dementia, and substance abuse. Approximately 70% of people with epilepsy have seizures that can be controlled by antiepileptic drugs; but in the United States, 80% of the cost of epilepsy can be attributed to the 30% of people with epilepsy whose seizures do not respond to medication. Their laboratories are carrying out both human and animal research aimed at understanding and treating those epileptic seizures for which current medications do not work. The most common cause of such medically refractory epileptic seizures is a condition known as mesial temporal lobe epilepsy, which is associated with a characteristic brain disturbance called hippocampal sclerosis.

Many patients with mesial temporal lobe epilepsy can be successfully treated by surgical removal of this brain abnormality and, at UCLA, these patients participate in a number of research projects designed to help them understand what causes hippocampal sclerosis and how hippocampal sclerosis causes epilepsy. Such studies are needed to develop new, more effective treatments for epilepsy and to prevent epilepsy. Parallel animal research is used to carry out additional studies that would be unethical, or prohibitively expensive, to pursue with patients and to identify fundamental neurobiological disturbances that can be validated by further testing with patients.

Their translational research ensures that insights gained from basic investigations at the systems, cellular, and subcellular levels can be rapidly and effectively applied to new concepts of diagnosis and treatment in the clinic and hospital. A large multidisciplinary team of basic and clinical neuroscientists is involved in this research, which takes advantage of unique opportunities to advance our knowledge about both normal and abnormal functions of the human brain, while at the same time providing beneficial services to their patients with epilepsy.

Neurobiological research on Aplysia, as well as on other organisms, is likely to lead to cures for neurodegenerative diseases related to memory, such as Alzheimer's, and to alleviating age-related memory loss. For example, it has recently been shown that a prion-like protein acts as a molecular switch for long-term memory in Aplysia. Malfunctioning prions in the human brain cause deadly neurodegenerative diseases, including mad cow disease. The work on Aplysia can therefore help us to understand what the normal function of prions is in the brain, and may suggest ways to prevent these proteins from behaving abnormally.

Carolyn R. Houser, Ph.D.
Professor of Neurobiology

Research Interests: Morphological Organization and Plasticity of the GABA System; and Neurochemical Anatomy of Temporal Lobe Epilepsy.

Research Overview

Much of the work in Dr. Houser's laboratory is focused on learning more about the basic mechanisms of epilepsy. In epilepsy, neurons in some specific regions of the brain, such as the hippocampus, become hyperexcitable and begin to be activated or “fire” in synchrony, thus producing spontaneous seizures or epilepsy. One of the major causes of epilepsy appears to be damage to the brain through severe, prolonged seizures or head trauma early in life. It then requires some time for spontaneous seizures to develop. Their goal is to identify the anatomical and neurochemical changes that occur between the initial insult and the subsequent development of epilepsy. Their broad hypothesis is that progressive changes in the GABA system, a major neurotransmitter system that normally helps inhibit or control excessive neuronal activity in the brain, are critical for the development of epilepsy.

By studying brain tissue from patients with epilepsy and related animal models, they have identified several interesting changes that could contribute to the development of seizure activity, and they are pursuing these findings. First, some but not all neurons that use GABA as their neurotransmitter are damaged in epilepsy. They are attempting to determine why some GABA neurons are easily damaged while others are spared. Since some GABA neurons remain, we are studying the changes that occur in these neurons, including the possible reorganization of their connections to other neurons. Finally, they are studying changes in the receptors through which GABA neurons influence the activity of other neurons. More detailed knowledge of such changes could lead to the development of new pharmacological methods for treating existing epilepsy, and, ultimately, for preventing the development of this disorder.

John K.H. Lu, Ph.D.
Professor of Obstetrics-Gynecology and Neurobiology

Neuroendocrinology of Reproduction

Dr. Lu's laboratory focuses on the neuroendocrine processes that lead to a decline in fertility during aging, in a process termed reproductive senescence. Reproductive senescence involves alterations in the events leading to reproductive function, and thus its onset impairs fertility. In young adult women, appropriate levels of estrogen and progesterone hormones are involved intricately in the CNS control of the menstrual cycle, and a normal reproductive cycle is required for a successful pregnancy to occur. Each month, a single egg is produced from developing structures in the ovary termed follicles. The total number of follicles that a woman has is already established during that individual's prenatal development, after which the number of follicles begins to decline steadily. Once an individual reaches the age of about 38 years, a much more rapid decrease in follicle numbers occurs, for reasons that are not well-understood. This sudden decline in the total number of follicles is also associated with a rapid decline in fertility, and is described as the perimenopause. Menopause occurs once the pool of follicles is exhausted, and reproductive function therefore ceases. Due to the demands of modern society, many individuals have delayed childbearing until the period of perimenopause, which begins at age 35. This change has led to an increase in age-related infertility. To understand how to promote fertility in individuals that are perimenopausal requires more information about the early reproductive aging process. In their laboratory the Long-Evans rat model of reproductive aging displays features that are also characteristic of human perimenopause. Middle-aged animals show a decrease in the hormone secretion required for appropriate ovulation at the time that fertility declines as well as changes in the timing of steroidogenesis during growth of the follicles, and altered ovulation. However, progesterone hormone treatment of young animals appears to enhance fertility when these animals reach middle age and, thus, may delay the onset of reproductive dysfunction. Therefore, the mechanism of progesterone treatment to preserve reproductive function of aging animals is an active area of research in their laboratory.

Paul Micevych, Ph.D.
Professor of Neurobiology and Surgery

The research of the Neuroendocrine Systems Laboratory is focused on steroid hormone interactions with the nervous system.   Throughout life, sex steroid hormones profoundly influence the structure and function of specific circuits that regulate reproduction and pain and mediate the ability of the brain to respond to injury (neuroprotection). Previously, they had focused on the steroid regulation of neuropeptide and transmitter expression. Currently, they are studying the mechanisms by which steroids affect the synthesis of sex steroids in the brain, cell signaling and neuroprotection. 

Regulation of Steroid Synthesis in the Brain

Two steroid hormones, estrogen and progesterone, modulate reproductive circuits in the brain. Both are produced by the ovary and as they recently determined, estrogen from the ovary stimulates progesterone synthesis in reproductively active female brain.  Post-menopausal rats lose the ability to make progesterone. Increased hypothalamic progesterone is restricted to the hypothalamus (a critical center for regulating motivated behaviors including reproduction and feeding) and is necessary for the initiation of the luteinizing hormone (LH) surge triggers ovulation.  Glial cells of the nervous system synthesize progesterone. Their findings affect the fundamental understanding of neural regulation of reproduction and reproductive aging.

Nongenomic Actions of Estrogen Modulation

The perception of pain is sexually dimorphic; however, the bases for this difference has eluded discovery. We have focused on estrogen and its ability to modulate response to painful stimuli (nociception). A series of experiments has demonstrated that estrogen acts not only in the brain and spinal cord but also directly on cells that register nociceptive signals (e.g., ATP). Estrogen modulates the response of these DRG (dorsal root ganglion) cells to ATP and to opioids which are internal anti-nociceptive signals. These experiments indicate that sex differences in pain responses are strongly influenced by estrogen. These experiments are expected to provide the experimental bases for the design of more appropriate therapies for treating pain in men and women.

Neuroprotection and Parkinson's Disease (PD)

PD, a neurodegenerative disorder, is characterized by progressive and massive loss of midbrain nigrostriatal dopaminergic (DA) neurons. The incidence and prevalence of PD is higher in men than in women. Post-menopausal women taking estrogen replacement therapy for a time continue to be protected against PD. We are studying how estrogen is neuroprotective of DA neurons in animal models of PD. To date, we have shown that estrogen acting through insulin-like growth factor-1 (IGF-1) provides dramatic protection during the acute phase of DA degeneration. Since PD is often associated with aging, we are studying age-related changes in the estrogen receptors and the IGF-1 system to determine if a contributing factor in PD may be the loss of the naturally occurring neuroprotection provided by estrogen and IGF-1. Discovery of natural neuroprotective mechanisms will contribute to therapies that harness the body's own defenses to prevent the onset of PD.

Michael Sofroniew, M.D., Ph.D.
Professor of Neurobiology

Injuries to the brain or spinal cord do not repair spontaneously. The work of the Sofroniew laboratory is directed at understanding the role of specific cell types in the response to injury in the brain and spinal cord and how the functions of these cells may be modified to improve outcome. In one project, using genetically modified mice, they have shown that one cell type, the astrocyte, has essential roles in protecting nerve cells after injury. They are currently investigating how these roles might be augmented to improve outcome after injury. In another project, they are investigating properties of neural stem cells that are present in the adult brain and how these cells might be harnessed for repair after brain injury.

Anna Taylor, Ph.D.
Professor of Neurobiology

The research of the Taylor laboratory addresses the question of how the brain is organized for coping with stress. They are particularly interested in the effects of stress on the neuroendocrine and neuroimmune systems. One of the stressors that they have been studying is alcohol exposure, both in pregnant rats and in adult rats. They have reported that maternal alcohol consumption during pregnancy leads to fetal alcohol effects that may manifest as inappropriate endocrine and behavioral responses to stress and immune dysfunction in the offspring. Continuous consumption of alcohol in adult rats also affects brain-immune interactions that become evident when the animal is challenged with an infectious agent, such as endotoxin. Their results point to interesting gender and strain differences in the neuroendocrine and neuroimmune responses to alcohol. Knowledge of the factors that mediate the developmental and long-term effects of alcohol exposure should contribute to understanding the risk for alcoholism in different individuals.

Joshua Trachtenberg, Ph.D.
Assistant Professor of Neurobiology

“The future ain't what it used to be.”

•  Yogi Berra

It is precisely because the future is unpredictable that the mammalian brain has evolved the capacity to rapidly acquire new information through sensory experiences, to store this information as memories, and to rapidly retrieve this information to modify behavior. But how do novel sensory experiences embed themselves in the fabric of the brain to form memories? This question drives the research in Dr. Trachtenberg's laboratory. His work focuses on understanding the cellular mechanisms of learning and memory in the mammalian cortex – a region of the brain that receives all sensory input, stores long-term memories and directs behavior by controlling motor output.

The specific issue that he pursues is the role of synapse formation and elimination in learning and memory. The cortex is an immensely complex circuit composed of billions of individual neurons that are precisely connected to each other through trillions of specialized contacts called synapses. A central tenet of neurobiology was that the precise pattern of synaptic connections in the adult cortex is fixed. That is, the neural circuitry in the cortex was thought to be “hard wired." His research demonstrated that this view is largely incorrect. His laboratory utilizes a newly-advanced technology, 2-photon laser scanning microscopy, to image single synapses in the living brain of mice, and to follow these same synapses day after day to determine their fate. Single neurons and their synaptic connections are visualized by labeling living neurons with a genetically-encoded fluorescent protein that emits green light when excited by the 2-photon laser. Using this approach, Dr. Trachtenberg observed that only about half the synapses onto a neuron are stable for months. The other 50% of synapses change over periods of days: new synapses form as others are eliminated. Changes in sensory experience modulate the rate of synaptic gain and elimination. Thus, adult cortical circuitry is far more labile than previously imagined. These were the first observations to document rapid changes in synaptic organization in the living, adult cortex. Furthermore, these observations provided the first empirical evidence in support of theoretical models showing that anatomical changes in synaptic organization underlie learning.

The future goal of his research is to investigate what determines whether a synapse is stabilized or eliminated, whether the fraction of stable and labile synapses changes with aging, and how specific diseases of the aging brain affect synapse stability in the cortex. Answers to these questions are critical to the development of rationally-based therapeutic approaches to prevent and treat diseases that destroy synapses in the cortex, including Alzheimer's, Parkinson's, and Huntington's disease.