Aging, Alzheimer's Disease, Brain, Cognitive Neuroscience, Cytoskeleton, Epigenetics, GABA, Glutamate (NMDA & AMPA) Receptors, Hormones, MRI, Membrane Proteins/Channels, Memory, Motor Neuron, Neural Networks, Neurobiology, Neuroscience, Neurotransmitters, Protein Trafficking & Sorting, RNA Transport & Localization, Receptors, Regeneration, Reproductive Biology, Signal Transduction, Synapses, Synaptic Plasticity, Synaptogenesis, Systems Neuroscience, Transgenic Mice, Transporters, Vision
PhD, Johns Hopkins University
Merit Award on Glutamate Receptors in Aging Cortical Circuits
Program Project Grant on Estrogen and the Aging Brain
Specific Clinical/Research Interest: Neurobiology of cognitive aging. Cortical organization, synaptic plasticity, and synaptic alterations with aging. Steroid effects on cortical circuitry, synaptic organization, and function. Neurodegeneration.
PhD: Sarah Motley, Yael Grossman. MD/PhD: Kimberly Kwei. Master: Thomas Chan.
Lab Manager: Bill Janssen; Research Assistants: Rishi Puri, Frank Yuk.
We work on synaptic plasticity, the aging brain, and the synaptic basis of age-related cognitive decline. We are particularly interested in the distinction between Alzheimer's disease (AD) and the more modest disruption of memory often referred to as age-associated cognitive impairment or mild cognitive impairment (MCI) that often occurs in the context of normal aging. While age-associated cognitive impairment represents a major health problem on its own that must be solved, preventing the transition from MCI to AD is a related goal of enormous importance given the rising threat and cost of AD to western society. In order to achieve either goal, we need to understand the cellular, synaptic, and molecular basis of the earliest age-related alterations that lead to cognitive decline and how these events relate to the complex physiology of aging, such as the aging of endocrine systems that affect the brain, or the interactions between stress and aging. For example, in AD, the cortical neurons that provide the complex connections that mediate cognition degenerate, leading to the catastrophic loss of cognitive function evident in dementia. Unlike AD, significant neuron death does not occur in normal aging and thus does not appear to be the cause of the initial stages of age-associated cognitive impairment. While these circuits do not die in normal aging, we have shown that they are vulnerable to sub-lethal age-related alterations in structure, synaptic integrity, and molecular processing at the synapse, all of which impair cognitive function in well-characterized animal models. In addition, while synapse loss occurs in aging, all synapses are not equally vulnerable and all regions do not age the same way. Our recent data on prefrontal cortex show that there is a selective loss of the class of synapses that is most plastic and likely to play a critical role in the cognitive processes mediated by prefrontal cortex, yet the age-related synaptic alterations in hippocampus are quite different, with minimal synapse loss. Biochemical alterations of the synapse, such as shifts in distribution or abundance of key neurotransmitter receptors, may also contribute to memory impairment, particularly in hippocampus.
We have shown that the same brain regions and circuits vulnerable to aging are responsive to circulating estrogen levels, suggesting that critical interactions between reproductive senescence and brain aging may affect excitatory synaptic transmission and cognitive performance. In fact, estrogen treatment in aged female monkeys protected the vulnerable class of synapses and restored cognitive performance to that of young monkeys. Importantly, the effects of estrogen on these neurons show that certain age-associated synaptic alterations may be reversible, leading to the protection of cognitive performance observed in these monkeys. These effects of estrogen give us a molecular and therapeutic entry point to explore additional interventions and strategies to protect against synaptic aging. If we can prevent the synaptic aging of these circuits while still largely intact, we may be able to protect individuals against the earliest stages of cognitive decline and in turn, prevent the transition to the death of these circuits that underlies AD.
A parallel area of research in our lab investigates the effects of behavioral stress on neurons in the prefrontal cortex. We have shown that stress leads to dendritic retraction on pyramidal neurons in prefrontal cortex, and this leads to cognitive decline. Importantly, if stress is discontinued these neurons recover, both structurally and functionally. In addition, the specific neuronal responses to stress differ between males and females. All of these studies were done in young animals, but recently, we were able to link our investigations into neuronal aging with our interest in behaviorally (i.e., stress)- induced plasticity. While the dendrites of prefrontal neurons in young animals recover from stress-induced retraction, this capacity for recovery is absent in middle-aged and aged animals. Furthermore, prefrontal neurons in middle-aged and aged rats lose spines with aging in the absence of stress and are further stress-induced synaptic loss or plasticity. We are now pursuing the mechanisms responsible for age-related loss of experience dependent plasticity.
Hara Y, Yuk F, Puri R, Janssen WG, Rapp PR, Morrison JH. Presynaptic mitochondrial morphology in monkey prefrontal cortex correlates with working memory and is improved with estrogen treatment. Proceedings of the National Academy of Sciences of the United States of America 2014 Jan; 111(1).
Young ME, Ohm DT, Janssen WG, Gee NA, Lasley BL, Morrison JH. Continuously delivered ovarian steroids do not alter dendritic spine density or morphology in macaque dorsolateral prefrontal cortical neurons. Neuroscience 2013 Dec; 255.
McEwen BS, Morrison JH. The brain on stress: vulnerability and plasticity of the prefrontal cortex over the life course. Neuron 2013 Jul; 79(1).
Baxter MG, Roberts MT, Gee NA, Lasley BL, Morrison JH, Rapp PR. Multiple clinically relevant hormone therapy regimens fail to improve cognitive function in aged ovariectomized rhesus monkeys. Neurobiology of aging 2013 Jul; 34(7).
Conley AJ, Stanczyk FZ, Morrison JH, Borowicz P, Benirschke K, Gee NA, Lasley BL. Modulation of higher-primate adrenal androgen secretion with estrogen-alone or estrogen-plus-progesterone intervention. Menopause (New York, N.Y.) 2013 Mar; 20(3).
Wang M, Yang Y, Wang CJ, Gamo NJ, Jin LE, Mazer JA, Morrison JH, Wang XJ, Arnsten AF. NMDA receptors subserve persistent neuronal firing during working memory in dorsolateral prefrontal cortex. Neuron 2013 Feb; 77(4).
Bloss EB, Puri R, Yuk F, Punsoni M, Hara Y, Janssen WG, McEwen BS, Morrison JH. Morphological and molecular changes in aging rat prelimbic prefrontal cortical synapses. Neurobiology of aging 2013 Jan; 34(1).
Hara Y, Morrison JH. Synaptic correlates of aging and cognitive decline. In: The Synapse: Structure and Function. (Pickel VM, Segal M, eds): Neuroscience-Net, LLC.; 2012.
Ohm DT, Bloss EB, Janssen WG, Dietz KC, Wadsworth S, Lou W, Gee NA, Lasley BL, Rapp PR, Morrison JH. Clinically Relevant Hormone Treatments Fail to Induce Spinogenesis in Prefrontal Cortex of Aged Female Rhesus Monkeys. The Journal of neuroscience : the official journal of the Society for Neuroscience 2012 Aug; 32(34).
Dumitriu D, Berger SI, Hamo C, Hara Y, Bailey M, Hamo A, Grossman YS, Janssen WG, Morrison JH. Vamping: stereology-based automated quantification of fluorescent puncta size and density. Journal of neuroscience methods 2012 Jul; 209(1).
Hara Y, Punsoni M, Yuk F, Park CS, Janssen WG, Rapp PR, Morrison JH. Synaptic distributions of GluA2 and PKMζ in the monkey dentate gyrus and their relationships with aging and memory. The Journal of neuroscience : the official journal of the Society for Neuroscience 2012 May; 32(21).
Dumitriu D, Laplant Q, Grossman YS, Dias C, Janssen WG, Russo SJ, Morrison JH, Nestler EJ. Subregional, dendritic compartment, and spine subtype specificity in cocaine regulation of dendritic spines in the nucleus accumbens. The Journal of neuroscience : the official journal of the Society for Neuroscience 2012 May; 32(20).
Miller MM, Morrison JH. Basal anxiety-like behavior predicts differences in dendritic morphology in the medial prefrontal cortex in two strains of rats. . Behav Brain Res. 2012 April; 229(1): 280-8.
Morrison JH, Baxter MG. The ageing cortical synapse: hallmarks and implications for cognitive decline.. Nat Rev Neurosci 2012; 13(4): 240-50.
Karatsoreos IN, Bhagat S, Bloss EB, Morrison JH, McEwen BS. Disruption of circadian clocks has ramifications for metabolism, brain, and behavior. Proc Natl Acad Sci USA 2011; 108(4): 1657-62.
Hara Y, Park CS, Janssen WG, Punsoni M, Rapp PR, Morrison JH. Synaptic characteristics of dentate gyrus axonal boutons and their relationships with aging, menopause, and memory in female rhesus monkeys. J Neurosci 2011; 31(21): 7737-7744.
Christoffel DJ, Golden SA, Dumitriu D, Robison AJ, Janssen WG, Ahn HF, Krishnan V, Reyes CM, Han MH, Ables JL, Eisch AJ, Dietz DM, Ferguson D, Neve RL, Greengard P, Kim Y, Morrison JH, Russo SJ. IkappaB kinase regulates social defeat stress-induced synaptic and behavioral plasticity. J Neurosci 2011; 31(1): 314-21.
Bloss EB, Janssen WG, Ohm DT, Yuk FJ, Wadsworth S, Saardi KM, McEwen BS, Morrison JH. Evidence for reduced experience-dependent dendritic spine plasticity in the aging prefrontal cortex. J Neurosci 2011; 31(21): 7831-7839.
Dumitriu D, Rodriguez A, Morrison JH. High throughput, detailed, cell-specific neuroanatomy of dendritic spines using microinjection and confocal microscopy. Nature Protocols 2011; 6(9): 1391- 1411 .
Dumitriu D, Hao J, Hara Y, Kaufmann J, Janssen WG, Lou W, Rapp PR, Morrison JH. Selective changes in thin spine density and morphology in monkey prefrontal cortex correlate with aging-related cognitive impairment. J. Neurosci 2010; 30(22): 7507-15.
Bloss EB, Janssen WG, McEwen BS, Morrison JH. Interactive effects of stress and aging on structural plasticity in the prefrontal cortex. J. Neurosci 2010; 30(19): 6726-31.
Shansky RM, Hamo C, Hof PR, Lou W, McEwen BS, Morrison JH. Estrogen Promotes Stress Sensitivity in a Prefrontal Cortex-Amygdala Pathway. Cerebral Cortex. Epub 2010 Feb;.
Goldwater DS, Pavlides C, Hunter RG, Bloss EB, Hof PR, McEwen BS, Morrison JH. Structural and functional alterations to rat medial prefrontal cortex following chronic restraint stress and recovery. Neuroscience 2009; 164: 798-808.
Radley JJ, Rocher AB, Rodriguez A, Ehlenberger DB, Dammann M, McEwen BS, Morrison JH, Wearne SL, Hof PR. Repeated stress alters dendritic spine morphology in the rat medial prefrontal cortex. J. Comp. Neurol 2008; 507(1): 1141-1150.
Yildirim M, Janssen WM, Tabori NE, Adams MM, Yuen GS, Akama KT, McEwen BS, Milner TA, Morrison JH. Estrogen and aging affect synaptic distribution of phosphorylated LIM kinase (pLIMK) in CA1 region of female rat hippocampus. Neuroscience 2008; 152(2): 360-370.
Hao J, Rapp PR, Janssen WM, Morrison JH, Lasley BL, Hof PR, Lou W. Interactive effects of age and estrogen on cognition and pyramidal neurons in monkey prefrontal cortex. Proc. Natl. Acad. Sci. USA 2007; 104: 11465-11470.
Morrison JH, Brinton RD, Schmidt PJ, Gore AC. Estrogen, menopause, and the aging brain: How basic neuroscience can inform hormone therapy in women. J. Neurosci 2006; 26(41): 10332-48.
Hao J, Rapp PR, Leffler AE, Leffler SR, Janssen WG, Lou W, Mc Kay H, Roberts JA, Wearne SL, Hof PR, Morrison JH. Estrogen alters spine number and morphology in prefrontal cortex of aged female rhesus monkeys. J Neurosci 2006; 26(9): 2571-2578.
Moga DE, Morrison JH, Shapiro ML. Bidirectional redistribution of AMPA but not NMDA receptors after perforant path stimulation in the adult rat hippocampus in vivo. Hippocampus 2006; 16(11): 990-1003.
Jacobsen JS, Wu CC, Redwine JM, Comery TA, Arias R, Bowlby M, Martone R, Morrison JH, Pangalos MN, Reinhart PH, Bloom FE. Early-onset behavioral and synaptic deficits in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci USA 2006; 103(13): 5161-5166.