neuro
MORRISON lab
LABORATORY FOR NEUROBIOLOGY OF AGING, PLASTICITy & CORTICAL ORGANIZATION


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. 

PUBLICATIONS

John H. Morrison, PhD
Dr. Morrison is Dean of Basic Sciences and the Graduate School of Biomedical Sciences, Professor in the Fishberg Department of Neuroscience and the Friedman Brain Institute, and the Willard T.C. Johnson Professor of Geriatrics and Palliative Medicine (Neurobiology of Aging).
journal of neuroscience 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).
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