Patrick R. Hof, MD
Laboratory of Neuromorphology
Our research is directed toward the study of selective neuronal vulnerability in dementing illnesses using classical neuropathological as well as modern quantitative immunohistochemical and neuronal imaging methods.
We intend to develop a quantitative, detailed, and cohesive definition of neuronal susceptibility to degeneration in the cerebral cortex by extending data on Alzheimer’s disease to other dementing disorders, as well as animal models of age-related illnesses, and by defining the key neurochemical and morphological characteristics linked to relative vulnerability (or resistance to degeneration) of identified neuronal populations.
The regional and laminar distribution in the cerebral cortex of specific neuronal populations is investigated in a variety of neurodegenerative disorders, and quantitatively compared to Alzheimer’s disease and control brains. In addition, a detailed study of brains from aged patients with no records of neurological and psychiatric disorders is performed in order to define further the limits of normal aging and longevity in the brain.
Dickstein DL, Kabaso D, Rocher AB, Luebke JI, Wearne SL, Hof PR. 2007. Changes in the structural complexity of the aged brain. Aging Cell 6:275-284.
Akram A, Christoffel D, Rocher AB, Bouras C, Kövari E, Perl DP, Morrison JH, Herrmann FR, Haroutunian V, Giannakopoulos P, Hof PR. 2008. Stereologic estimates of total spinophilin-immunoreactive spine numbers in area 9 and the CA1 field: relationship with the progression of Alzheimer’s disease. Neurobiol Aging 29:1296-1307.
Kabaso D, Coskren PJ, Henry BI, Hof PR, Wearne SL. 2009. The electrotonic structure of pyramidal neurons contributing to prefrontal cortical circuits in macaque monkeys is significantly altered in aging. Cereb Cortex 19:2248-2268.
Mark G. Baxter, PhD
The Glickenhaus Laboratory of Neuropsychology
Research in the Baxter laboratory focuses on the neural mechanisms of learning, memory, executive function, and decision-making, and the ways in which these mechanisms fail in aging and neuropsychiatric disorders.
The laboratory’s research on aging takes two approaches. First, neuropsychological studies in young animals form a basis for probing the function of defined neural systems in the aging brain. For example, development of an attentional shifting task that is impaired by damage to frontoparietal circuitry in young rats allows this task to be used to test the integrity of this circuitry in aging rats. This also provides a basis for correlating structural and neurochemical measures of brain function with behavioral output.
Second, the laboratory is interested in treatments that may modify the course of cognitive aging. This includes the involvement of acetylcholine and other neuromodulators in responses to neural injury and neurodegeneration, as well as the role of ovarian steroid hormones in cognitive and neurobiological aging.
The overarching goal of the research in the laboratory is to translate findings from basic behavioral and cognitive neuroscience into an improved understanding of disorders of cognition in humans, and to help develop therapeutic strategies for maintaining and improving cognitive function in aging and neurological diseases.
Baxter MG, Parker A, Lindner CCC, Izquierdo AD, Murray EA. 2000. Control of response selection by reinforcer value requires interaction of amygdala and orbital prefrontal cortex. J Neurosci 20:4311-4319.
Barense MD, Fox MT, Baxter MG. 2002. Aged rats are impaired on an attentional set-shifting task sensitive to medial frontal cortex damage in young rats. Learn Mem 9:191-201.
Baxter MG. 2009. Involvement of medial temporal lobe structures in memory and perception. Neuron 61:667-677.
Browning PGF, Gaffan D, Croxson PL, Baxter MG. 2009. Severe scene learning impairment, but intact recognition memory, after cholinergic depletion of inferotemporal cortex, followed by fornix transection. Cereb Cortex Epub 15 May 2009.
Dara Dickstein, PhD
Neurobiology of Aging and Neurodegeneration
Research in the Dickstein lab focuses on the structural changes on neurons with ageing and disease. Our main research interests focus on Alzheimer’s disease and Parkinson’s disease, specifically targeting cells of the hippocampus and prefrontal cortex, areas crucial for cognition. We also investigate the effects of cancers and chemotherapy on neuronal and synapse integrity. We use a combination of transgenic mouse models, neuroanatomy, and confocal and electron microscopy to analyze the changes that neurons and synapses undergo during disease.
Charles V. Mobbs, PhD
Laboratory of Aging and Metabolism
A key observation about the nature of age-related impairments is that these impairments accrue over time, reflecting a cumulative and apparently irreversible process. We have now discovered the molecular mechanism of this "molecular memory" effect and shown that it applies to all age-related diseases that are influenced by dietary restriction.
In particular, this process explains the cumulative development of diabetic complications, and implies that both age-related impairments and diabetic complications can not only be slowed (as with dietary restriction) but can actually be reversed, by blocking glucose metabolism more effectively than can be done with dietary restriction.
A key element of this mechanism is the induction of a transcriptional complex including the transcriptional co-activator CBP. This complex appears to mediate the protective effects of dietary restriction as well as the effects of the insulin-like receptor (daf-2 in C. elegans) on aging and expression of protective genes such as superoxide dismutase sod-3.
Yen K, Mobbs CV. 2008. Chemosensory and caloric mechanisms influence distinct components of mortality rate. Exp Gerontol 43:1058-1060.
Yen K, Steinsaltz D, Mobbs CV. 2008. Validated analysis of mortality rates demonstrates distinct genetic mechanisms that influence lifespan. Exp Gerontol 43:1044-1051.
Zhang M, Poplawski M, Yen K, Cheng H, Bloss E, Zhu X, Patel H, and Mobbs CV. 2009 Role of CBP and SATB-1 in aging, dietary restriction, and insulin-like signaling. PLoS Biol 7(11):e1000245.
Our laboratory is focused primarily on determining the molecular and structural nature of age-related alterations in synaptic plasticity that lead to compromised cognitive function. Our studies are directed primarily at prefrontal cortex and hippocampus of primates and rodents.
In contrast to Alzheimer's disease, neuron death is not likely to be a significant contributor to functional decline in normal aging. Shifts in expression and distribution of key molecules (i.e., glutamate receptors) in otherwise intact circuits, however, do appear to be occurring in aging, and in a manner that would have profound effects on synaptic transmission and plasticity in relevant hippocampal and neocortical circuits.
These alterations in the molecular constituents of the synapse occur against a background of structural alterations of the spines and synapses that also impact function. Our interests in aging and synaptic plasticity have been expanded over the years to include research programs on the effects of stress on cortical function and plasticity, as well as the links between neuronal aging and endocrine senescence.
With respect to stress, we have revealed stress-induced alterations in neuronal structure that are reversible, and we are now focusing on how such plasticity relates to gender and aging.
Our studies on estrogen have revealed synaptic attributes in monkey prefrontal cortex that are altered with aging yet rescued by estrogen treatment, thereby protecting against cognitive decline in aged female monkeys. In addition, just as selective vulnerability is reflected in which cell types degenerate in Alzheimer's disease, all synapses are not equally vulnerable to aging, with the most plastic synapses exhibiting the highest level of vulnerability.
Through comprehensive morphologic and molecular analyses of behaviorally characterized rats and nonhuman primates, we are able to link quantitative cellular, molecular, and synaptic measurements to cognitive performance, thereby revealing the precise synaptic attributes that correlate with performance and need to be preserved to retain cognitive function. Such studies will lay the groundwork for new therapeutic approaches to age-related cognitive decline and Alzheimer's disease.
Hao J, Rapp PR, Leffler AE, Leffler SR, Janssen WGM, Lou W, McKay H, Roberts JA, Wearne SL, Hof PR, Morrison JH. 2006. Estrogen alters spine number and morphology in prefrontal cortex of aged female rhesus monkeys. J Neurosci 26:2571-2578.
Hao J, Rapp PR, Janssen WGM, Lou W, Lasley BL, Hof PR, Morrison JH. 2007. Interactive effects of age and estrogen on cognition and pyramidal neurons in monkey prefrontal cortex. Proc Natl Acad Sci USA 104:11465-11470.
Goldwater DS, Pavlides C, Hunter RG, Bloss EB, Hof PR, McEwen BS, Morrison JH. 2009. Structural and functional alterations to rat medial prefrontal cortex following chronic restraint stress and recovery. Neuroscience 164:798-808.
Matthew L. Shapiro, PhD
Laboratory of Cognitive and Behavioral Neuroscience of Memory
Our laboratory focuses on how the brain remembers — how specific neural circuits support memory in the everyday sense of the word. People normally remember where they park their cars, and "losing one's car" is a common complaint early in Alzheimer's disease.
Like people, animals learn about and remember important places and events, and use homologous neural networks. Our laboratory investigates neural network function in rats by combining brain manipulations, behavioral tests that require memory, and electrophysiological methods that can identify and alter neuronal activity patterns needed for memory-guided behavior. The long-term goal is to understand these basic mechanisms sufficiently to repair damaged and enhance normal human memory.
Shapiro ML, Ferbinteanu J. 2006. Relative spike timing in pairs of hippocampal neurons distinguishes the beginning and end of journeys. Proc Natl Acad Sci USA 103:4287-4292.
Kennedy PJ, Shapiro ML. 2009. Motivational states activate distinct hippocampal representations to guide goal-directed behaviors. Proc Natl Acad Sci USA 106:10805-10810.
Rich EL, Shapiro ML. 2009. Rat prefrontal cortical neurons selectively code strategy switches. J Neurosci 29:7208-7219.
Joseph D. Buxbaum, MSc, PhD (Psychiatry)
Patrizia Casaccia MD (Neuroscience)
Kenneth L. Davis, MD (Psychiatry)
Lakshmi Devi, MSc, PhD (Pharmacology and Systems Therapeutics)
Dara L. Dickstein, PhD (Neuroscience)
Rita De Gasperi, PhD (Psychiatry)
Michelle Ehrlich, MD (Neurology)
Gregory Elder, MD (Psychiatry)
Zahi Fayad, PhD (Radiology)
Samuel Gandy, MD, PhD (Neurology)
Anastasios Georgakopoulos, PhD (Psychiatry)
Vahram Haroutunian, PhD (Psychiatry)
Giulio-Maria Pasinetti, MD, PhD (Neurology)
Daniel P. Perl, MD (Pathology)
Dushyant P. Purohit, MD (Pathology)
Nikolaos Robakis, PhD (Psychiatry)
Miguel Gama Sosa, PhD (Psychiatry)
Takeshi Sakurai, MD, PhD (Psychiatry)
Cheuk Y. Tang, PhD (Radiology)
Zhenyu Yue, PhD (Neurology)
Mary Sano, PhD (Psychiatry)
Jin Fan, PhD (Psychiatry)
Thomas P. Naidich, MD (Radiology)
Burton Drayer, MD (Radiology)
Fred Lublin, MD (Radiology)
Kristjan Ragnarsson, MD (Rehabilitation Medicine)
Jeremy Silverman, PhD (Psychiatry)
Hillel Grossman, MD (Psychiatry)
Michal Schnaider-Beeri, PhD (Psychiatry)
Margaret Sewell, PhD (Psychiatry)
Jeffrey Silberstein (Executive Vice President Msmc President's Office)