Nancy EJ Berman - US grants

The long term objectives of the proposed research are to understand the role of the earliest born neurons in histogenesis of the cerebral cortex. The hypotheses that the earliest born neurons are unique, that they play a role in establishment of cortical connectivity, and that they are involved in establishment of differences among cortical areas will be tested Development of normal cortical function requires proper development of neuronal connectivity and transmitter expression. Interference with the normal sequence of events during any phase of cortical development can result in behavioral and cognitive disabilities ranging from subtle to severe. The proposed studies will focus on the earliest born neurons of the cerebral cortex. The timing and rate of neuron death in the earliest born neurons will be compared with the timing and rate of neuron death in two later born populations. The neurotransmitter and/or neuropeptide expressed by the earliest born neurons which die and those which survive will be examined to determine whether and when specific neuronal populations are selectively eliminated. To determine whether the earliest born neurons may be involved in specification of cortical areas, developmental patterns of expression of neuropeptides in 5 well-defined cortical areas will be compared. The population of neurons which participate in the initial formation of the callosal pathway will be identified, and the potential role of particular neurotransmitters or neuropeptides in growth cone guidance and axon branching will be assessed. The timing and extent of exuberance in the supragranular and infragranular callosal cells will be examined to determine whether or not axon withdrawal occurs in the neurons which pioneer the callosal pathway. Experiments will be done to determine whether or not callosal axons reach the contralateral hemisphere before their parent cell bodies complete migration, and whether not the neurons which send out the first callosal axons subsequently die.

The major question addressed by Dr. Berman's studies is how the brain processes information given to it by the eyes. As scientists have learned more about how vision occurs, it has become clear that there are separate systems for processing particular types of information, such as pattern, color and motion, which can be identified at all levels of the visual pathways including the retina. In the retina, certain cells are specialized to detect particular types of stimuli in the visual world. These cells send information to particular regions of the brain which are specialized in processing the same type of information. The two major types of retinal cells are the "on-center" cell, which detects light objects on a dark background, and the "off-center" cell, which detects dark objects on a light background. In the retina, these cells are anatomically distinct, and each type is organized to allow it to "see" the complete visual environment independently of the other type. The major goal of Dr. Berman's work will be to learn how on-center and off-center information is processed in the region of the brain which receives this retinal information, the lateral geniculate nucleus. Dr. Berman will use anatomical and physiological methods to study the detailed arrangement of these cell types in this nucleus. This will provide basic information on how the brain processes information about contrast, an essential function for normal vision.

Traumatic brain injury initiates a sequence which includes both beneficial and detrimental events. Injury to the cerebral cortex results in rapid degeneration of thalamic neurons which are not available for reconnection to undamaged cortex. Microglia are key cells in the response to brain injury. Monocyte-chemoattractant-protein-1 undamaged cortex. Microglia are key cells in the response to brain injury. Monocyte-chemoattractant-protein-1 (MCP-1) is a chemokine expressed following injury which attracts microglia and other cells of the monocyte lineage. Preliminary experiments have identified rapid expression of MCP-1 in the thalamus following cortical lesions. The hypothesis is that MCP-1 is the critical molecule in modulation brain repair responses. In this proposal, induced mutants/genetic models of brain-targeted MCP-1 over-expression, knockout of MCP-1, and knockout of the high affinity MCP-1 receptor (CCR2), will provide in vivo modulation of MCP-1. The proposed experiments will examine the extend and temporal pattern of axotomized neuron death and of microglial migration, activation and proliferation in the thalamus. The following specific aims are proposed 1) To determine the effect of brain-targeted over- expression of MCP-1 on degeneration of thalamic neurons following cortical injury, 3) to determine the effect of ablation of MCP-1 and of its high affinity receptor, CCR-2, on degeneration of thalamic neurons following cortical injury, 4) to determine the effect of genetic manipulation of MCP-1 and its receptor n monocyte trafficking and microglial migration following cortical lesions. Understanding the role of MCP-1 in attracting of monocytes and microglial to sites of damage, and in activation of these cells, may lead to determination of targets for therapies for treatment for brain injury.

[unreadable] DESCRIPTION: Temporomandibular joint pain is two to three times more common in women than in men, and symptoms are often associated with natural changes in levels of ovarian steroids. Preliminary experiments have demonstrated that galanin, neuropeptide Y and tryptophan hydroxylase are regulated by ovarian steroids in trigeminal ganglia. The overall hypothesis of this application is that ovarian steroids regulate the phenotype of trigeminal neurons by acting upon estrogen receptors during the natural estrous cycle, following ovariectomy and during pregnancy. We will examine 3 stages of the natural cycle, proestrus, when estrogen levels are highest, estrus, when estrogen levels are falling, and diestrus, when estrogen levels are low. We will study pregnant mice, when estrogen levels are stable and high, and ovariectomy, when estrogen levels are stable and low. We will use hormone replacement to determine if the changes are due to estrogen. Responses of the estrogen receptor in regulating gene expression during the natural estrous cycle will be assessed in a transgenic mouse that expresses a luciferase reporter gene under the control of activated estrogen receptors (ERE-luc mice). In Specific Aim 1, we will determine whether trigeminal neurons innervating the TMJ express estrogen receptors, and whether trigeminal neurons increase expression of genes with estrogen response elements in phase with the natural estrous cycle. In Specific Aim 2, we will determine whether the cyclical hormonal changes of the natural estrous cycle and the constant high levels during pregnancy or low levels following ovariectomy alter expression of trigeminal genes involved in nociception and inflammation. In Specific Aim 3, we will examine the effects of ovarian steroids on TMJ and trigeminal responses to TMJ inflammation. These experiments will provide an innovative approach to the mechanism of hormonal regulation of facial pain. [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) is a leading cause of disability in the elderly. The outcome of a similar injury is worse in the elderly than in younger adults, but the mechanisms underlying this difference are unknown. An interdisciplinary research team including a biomedical engineer with expertise in high field strength MRI, an expert on human TBI, and a neuroscientist with expertise in molecular and behavioral neuroscience will address the hypothesis that increased inflammatory responses to a comparable injury in old mice contribute to the worsened outcome. The experiments test the specific mechanistic hypothesis that in old mice, an increased inflammatory response causes increased activation of the extrinsic apoptosis pathway and increased activation of stress kinase JNK, both of which result in increased secondary neuron death. Preliminary data support this hypothesis by demonstrating higher expression of proinflammatory genes in old than in adult mice during secondary neuron death. Two specific aims are proposed to test this hypothesis: 1) Develop a model of mild controlled cortical impact (CCI) in mice to model contusional TBI, characterize initial behavioral deficits and recovery using cognitive and motor tests, characterize tissue damage and neuron death after CCI in adult and old mice by MRI, histology and unbiased stereology, and assays of activation of the effector caspase-3, and 2) Characterize the inflammatory response by measuring expression of proinflammatory genes including MCP-1, TNF-alpha, and IL-1beta in cortex, hippocampus and thalamus, determine whether the response to CCI in old mice involves increased activation of the stress kinase JNK, and determine whether the response to CCI in old mice involves increased activation of the extrinsic apoptosis pathway via caspase-8. The overall goal of these studies is to provide a rationale for specific treatments for TBI in the elderly. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Elderly patients who suffer traumatic brain injury (TBI) have increased mortality and survivors have a poorer prognosis than young or middle aged adults who suffer comparable injuries. We have demonstrated that the aging brain is in a hyperinflammatory state before any injury, that the inflammatory response after brain injury is exaggerated, and that both edema and blood brain barrier disruption are increased after TBI in the aged brain. The proposed experiments test the specific hypothesis that increased matrix metalloproteinase (MMP) activity worsens blood brain barrier disruption and causes increased edema after TBI in the aged brain, leading to increased death of neurons and poor behavioral recovery. An interdisciplinary research team including a neuroscientist with expertise in molecular and behavioral neuroscience and neuroanatomy, an MRI physicist, and an expert in pharmacokinetics will test this hypothesis using the controlled cortical impact (CCI) model of TBI in mice. The specific aims are 1) to determine whether CCI results in increased MMP-2 and MMP-9 activity in aged mice, 2) to determine whether blood brain barrier disruption, edema, and neuron death are greater after CCI in aged mice leading to poor behavioral recovery, and 3) to determine whether reducing MMP activity improves outcomes. The overall goal of these studies is to provide a rationale for specific treatments to improve outcomes of TBI in the elderly and to test effectiveness of treatments based on this rationale. PUBLIC HEALTH RELEVANCE: Elderly patients who suffer traumatic brain injury have increased mortality, and survivors have a poorer prognosis, than younger adults who suffer comparable injuries. The goal of this research program is to understand the reason for these poor outcomes and to provide new treatment strategies using an animal model.