Neuroscience Graduate Program at UCSF
Brain Injury, Neuroinflammation and Cognitive Function
Cognitive impairments develop in response to a variety of insults to the CNS including disease or injury and constitute a significant factor with respect to overall function and quality of life. The pathogenesis of cognitive deficits is poorly understood and likely multifaceted. In particular, my lab is focused on elucidating how injury-induced alterations in neurogenesis, innate immune response, oxidative stress, post transcritpition/translational modifications, and chronic neuroinflammation affect various neural processes underlying cognitive function.
To examine the above effects, my laboratory employs three principle animal models: controlled cortical impact model of traumatic brain injury (TBI), therapeutic cranial γ-irradiation, and ionizing irradiation (HZE). Within these animal models we also examine multiple genotypes including CCR2rfp/+CX3CR1gfp/+, CCR2rfp/rfp,, CX3CR1gfp/gfp , TNFR1-/- mice, and McGill hAβPP rats. Our ultimate goal is to understand the mechanisms responsible for the cognitive dysfunction associated with neurodegenerative diseases, such as Alzheimer's disease, fronto-temporal dementia and other neurological-related disorders.
Our published results demonstrate that neuroinflammation alters the coupling of neuronal activity with the transcription of genes that are implicated in long term memory and synaptic plasticity. The behaviorally-induced immediate early gene (IEG) Arc (activity-regulated cytoskeleton-associated protein) is dynamically induced in response to neuronal activity and is required for synaptic plasticity and memory consolidation. Arc expression can be utilized to map neuronal networks that underlie information processing and plasticity. We have been able to characterize the kinetic of Arc expression in the different hippocampal subregions (CA1, CA3 and DG). We recently demonstrated a unique kinetic profile for Arc transcription in hippocampal granule neurons following behavior that is not observed in other cell types. Among a number of possibilities, this sustained transcription may provide a mechanism that ensures that the synaptic connection weights in the sparse population of granule cells recruited during a given behavioral event are able to be modified.
Our analyses of chronic neuroinflammation suggest that the depletion of the synaptic activity-dependent protein Arc play a critical role in cognitive decline. Using different animal models of chronic neuroinflammation and Alzheimer’s disease we have recently demonstrated that inhibiting the translation of pro-inflammatory Tumor Necrosis Factor alpha (TNF-alpha) we were able to ameliorate treatment-induced cognitive dysfunction.
We are able to study hippocampal neuronal network’s activity using the IEG based brain-imaging method called catFISH (cellular compartment analysis of temporal activity using fluorescence in situ hybridization). This method capitalizes upon the sub-cellular localization of IEG mRNA, which is dynamically coupled to neural activity associated with attentive, active behavior. When neurons are engaged in such information processing, they rapidly transcribe IEGs at individual alleles within the nucleus – visible for ~5 minutes as bright transcription foci. Subsequently, the mRNA is transported to the cytoplasm, peaking in concentration at ~30 min. This method allows the resolution of two distinct cellular compartments, making it possible to identify which neurons were active during two behavioral epochs. Thus, catFISH provides repeated neuronal activity measurements in the same subject, with the cellular resolution to delineate neural networks engaged in specific behaviors. With this innovative method we can detect primary transcripts at the genomic alleles; this provides excellent temporal and cellular resolution and facilitates mapping of neuronal activity (Rosi et al., Brain 2009). Given that catFISH data have been corroborated using parallel electrophysiological studies, this method provides us an innovative way to evaluate the reliability of hippocampal neuronal networks. To this extent, we have been able to document a significant correlation between the presence of chronic neuroinflammation and altered hippocampal networks activity.
Recent work has shown that injury-induced activation of the brain’s resident macrophage (microglia) occurs rapidly after injury but can persist for months and even years in humans. As a consequence of protracted activation, microglia may contribute to the neurodegenerative sequelae following brain injury. This response is often associated with the recruitment of blood-born macrophages from the periphery which migrate into the injured brain parenchyma Moreover, given that upon activation microglia phenotypically resemble peripheral macrophages in function and appearance it is difficult to delineate the role of peripheral immune macrophages in brain injury. In order to define the central (microglia) versus peripheral (macrophage) immune effect in brain injury, my lab uses the unique CCR2rfp/+CX3CR1gfp/+reporter mice to reliably demarcate these two innate immune cell populations.
My laboratory uses a battery of behavioral tests to discriminate the functionality of specific brain regions: radial arm water maze (hippocampus), novel place and novel object recognition (hippocampus vs non-hippocampus), social behavior (prefrontal cortex), metric distance (dentate gyrus), set shifting paradigm (infralimbic and paralimbic prefrontal cortex), elevated plus maze (prefrontal cortex and hippocampus).
Ongoing studies, funded by the National Institute of Aging (NIA), the National Cancer Institute (NCI) the National Aeronautics and Space Administration (NASA), and the Alzheimer’s Association are aimed to:
Josh Morganti, Ph.D.
Austin Chou, Neuroscience Graduate Student
Timothy Jopson, Research Assistant
Lara Riparip, Research Assistant
Rosi S, Ramirez-Amaya V, Vazdarjanova A, Worley PF, Barnes CA, Wenk GL. Neuroinflammation alters the pattern of behaviorally induced Arc in the hippocampus (2005) Journal of Neuroscience. 25(3): 723-731.
Ramirez-Amaya V, Vazdarjanova A, Mikael D, Rosi S, Worley PF, Barnes CA. Coordinate Arc mRNA and protein expression in the neuronal networks activated by spatial exploration (2005) Journal of Neuroscience. 25(7): 1761-1768.
Rosi S, Andres-Mach M, Fishman K, Ferguson R, Levy W, Fike JR. Cranial irradiation alters the behaviorally-induced immediate early gene Arc (activity-regulated cytoskeleton-associated protein) (2008) Cancer Research, Dec 1; 68 (23):9763-70. [PMCID: PMC2597278]
Rosi S, Ramirez-Amaya V, Vazdarjanova A, Esperanza EE, Larkin P, Fike JR, Wenk GL, Barnes CA. Accuracy of hippocampal network activity is disrupted by neuroinflammation: rescue by memantine (2009) Brain; 132:2464-77. [PMCID: PMC2732266]
Belarbi K, Arellano C, Ferguson R, Jopson T, Rosi S. Chronic neuroinflammation impacts the recruitment of adult-born neurons into behaviorally relevant hippocampal networks. Brain Behav Immun. 2012 Jan;26(1):18-23. Epub 2011 Jul 20.
Rosi S, Ferguson R, Fishman K, Raber J, Fike RJ. The polyamine inhibitor α-Difluoromethylornithine modulates hippocampus-dependent function after single and combined injuries. PlosOne 2012;7(1):e31094. Epub 2012 Jan 27.
Belarbi K, Jopson T, Tweedie D, Arellano C, Luo W, Greig NH, Rosi S. TNF-α protein synthesis inhibitor restores neuronal function and reverses cognitive deficits induced by chronic neuroinflammation. J of Neuroinflammation. 2012 Jan 25;9:23.
Belarbi K, Jopson T, Arellano C, Rosi S. CCR2 deficiency prevents neuronal dysfunction and cognitive impairments induced by cranial irradiation. Cancer Research, 2013 Feb 1;73(3):1201-10. doi: 10.1158/0008-5472.CAN-12-2989. Epub 2012 Dec 13.
Ramirez-Amaya V, Argulo P, Chawla M, Barnes C, Rosi S. Sustained transcription of the immediate early gene Arc in the dentate gyrus after spatial exploration. Journal of Neuroscience, 2013 Jan 23;33(4):1631-1639.
Susanna Rosi, Ph.D.
San Francisco General Hospital
Brain and Spinal Injury Center
1001 Potrero Avenue, Building 1, room 242
San Francisco, CA 94133