The Silva Lab

Our Research

Anatomical Organization of the Primate Brain

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Our laboratory is interested in developing and utilizing MRI techniques that allow visualization of the rich anatomy of the primate brain. The main results from this work have been on the use of multi-modal MRI pulse sequences that include manganese-enhanced MRI, T1-weighted, T2-weighted, T2*-weighted, diffusion tensor and susceptibility-weighted imaging to enhance the rich brain’s cytoarchitecture according to cell density, myelination, fiber orientation or cerebral microvasculature contrast. This work has been performed in strong collaboration with other laboratories, and serves as a great example of the highly interactive collaboration at NIH. The data acquired has been of great value to inform on what we call the “functional/anatomical” parcellation of the cortex, and applications include using the high-resolution anatomical images to generate an MRI-based atlas for the marmoset brain that serves as a template upon which other neuroimaging data can be registered to, to presurgical planning, to understanding how changes in size and borders of the areas after stroke or denervation report on the plasticity of the brain.

  • Silva AC. Anatomical and functional neuroimaging in awake, behaving marmosets. Dev Neurobiol. 2017 Mar;77(3):373-389. PubMed PMID: 27706916; PubMed Central PMCID: PMC5318267.d. Sati P, Silva AC, van Gelderen P, Gaitan MI, Wohler JE, Jacobson S, Duyn JH, Reich DS. In vivo quantification of T₂ anisotropy in white matter fibers in marmoset monkeys. Neuroimage. 2012 Jan 16;59(2):979-85. PubMed PMID: 21906687; PubMed Central PMCID: PMC3230780.

Functional Organization of the Primate Brain

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We want to understand how the spatial localization and temporal evolution of the HRF to functional brain stimulation relate to the anatomical organization of the brain, in particular, to cortical cytoarchitecture (see Anatomical Organization of the Primate Brain Anatomy above). At a macroscopic scale, fMRI data is obtained to study the spatial and temporal aspects of the hemodynamic response function (HRF) and their relationship to ongoing neural activity. To probe brain function, we use both resting-state and task-based fMRI methods. This approach will lead to the identification of the true spatial extent of the HRF and provide significant insight into the functional spatiotemporal specificity of the cerebral microcirculation.

Development of Genetically Engineered Marmoset Models of Brain Function and Neurological Disorders.

The use of non-human primates in biomedical research is essential to understanding physiological and pathological processes in the highly evolved human brain. We have generated transgenic marmosets expressing genetically encoded calcium indicators such as GCaMP5G/6s that constitute a much-improved animal model for studying brain function in relevant translational conditions. We have also produced a mutant marmoset model of Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), the most frequent of the genetic small vessel diseases. Data obtained from genetically engineered marmosets are likely to offer new insights into the molecular and genetic mechanisms of neurological disorders and contribute to developing novel biomarkers and therapeutical approaches with higher translational impact.

Manganese-Enhanced MRI (MEMRI)

Our Principal Investigator, Afonso Silva, has been involved with the development of MEMRI since its inception in the late 1990s, and made significant contributions to its implementation and optimization in studies of brain anatomy and function. The divalent ion Mn2+, which acts as a biological calcium analog, can enter excitable cells in the central nervous system (CNS) and act as a polysynaptic anterograde neuronal tract tracer. This allows makes a particularly attractive contrast agent for MRI of the brain, and 3 major classes of applications of MEMRI have materialized: First, systemic administration of Mn2+ has opened up new MRI-based strategies for enhancement of the cerebral neuroarchitecture, leading to unique MRI enhancement in specific areas of the brain. Second, Mn2+ moves anterogradely along appropriate neuronal pathways when injected to specific brain regions, allowing MEMRI to map neuronal tracts in the living brain. Third, due to the ability of Mn2+ to enter excitable cells through voltage-gated calcium channels, MEMRI can be used to demarcate active regions of the brain, providing an attractive means to probe cerebral function with a hemodynamic-independent contrast. In the present project, we will perform MnCl2 injections into specific regions of the marmoset brain to trace cortico-cortical, cortico-thalamic and cortico-cerebellar projections using high-resolution whole-brain MEMR

  • Silva AC. Using manganese-enhanced MRI to understand BOLD. Neuroimage. 2012 Aug 15;62(2):1009-13. PubMed PMID: 22245640; PubMed Central PMCID: PMC3355203.  
  • Bock NA, Kocharyan A, Silva AC. Manganese-enhanced MRI visualizes V1 in the non-human primate visual cortex. NMR Biomed. 2009 Aug;22(7):730-6. PubMed PMID: 19322808; PubMed Central PMCID: PMC3133650.  
  • Silva AC, Bock NA. Manganese-enhanced MRI: an exceptional tool in translational neuroimaging. Schizophr Bull. 2008 Jul;34(4):595-604. PubMed PMID: 18550591; PubMed Central PMCID: PMC2632451.  
  • Bock NA, Paiva FF, Silva AC. Fractionated manganese-enhanced MRI. NMR Biomed. 2008 Jun;21(5):473-8. PubMed PMID: 17944008; PubMed Central PMCID: PMC4748952.  

Transgenic Marmosets & Gene Editing

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Understanding the Mechanisms of Neurological Diseases.

Related to the use of genetically engineered animal models of neurological disorders, our laboratory is also interested in understanding the mechanisms of CBF regulation during pathological brain states, including hypertension and stroke. The primary approach has been to investigate how hypertension and stroke alter the function of the neurovascular unit and thus change the spatiotemporal characteristics of neurovascular coupling and potentially determine critical molecular pathways that could be the target of therapeutical strategies. 

  • Donadieu M, Kelly H, Szczupak D, Lin JP, Song Y, Yen CCC, Ye FQ, Kolb H, Guy JR, Beck ES, Jacobson S, Silva AC, Sati P, Reich DS. Ultrahigh-resolution MRI Reveals Extensive Cortical Demyelination in a Nonhuman Primate Model of Multiple Sclerosis. Cereb Cortex. 2021 Jan 1;31(1):439-447. doi: 10.1093/cercor/bhaa235. PubMed PMID: 32901254; PubMed Central PMCID: PMC7947170. 
  • Szczupak D, Yen CC, Liu C, Tian X, Lent R, Tovar-Moll F, Silva AC. Dynamic Interhemispheric Desynchronization in Marmosets and Humans with Disorders of the Corpus Callosum. Front Neural Circuits. 2020;14:612595. doi: 10.3389/fncir.2020.612595. eCollection 2020. PubMed PMID: 33408615; PubMed Central PMCID: PMC7779638. 
  • Leibovitch EC, Caruso B, Ha SK, Schindler MK, Lee NJ, Luciano NJ, Billioux BJ, Guy JR, Yen C, Sati P, Silva AC, Reich DS, Jacobson S. Herpesvirus trigger accelerates neuroinflammation in a non-human primate model of multiple sclerosis. Proc Natl Acad Sci U S A. 2018 Oct 30;115(44):11292-11297. PubMed PMID: 30322946; PubMed Central PMCID: PMC6217390.  
  • Choi SH, Arai AL, Mou Y, Kang B, Yen CC, Hallenbeck J, Silva AC. Neuroprotective Effects of MAGL (Monoacylglycerol Lipase) Inhibitors in Experimental Ischemic Stroke. Stroke. 2018 Mar;49(3):718-726. PubMed PMID: 29440474; PubMed Central PMCID: PMC5829008.  

The Silva Lab

A Neurobiology Lab at the University of Pittsburgh