The long-term goal of our research is to construct and characterize a realistic three-dimensional model of the brain extracellular space (ECS), in order to predict the impact of microstructural changes on the transport of signaling molecules, nutrients and therapeutic agents. ECS comprises the narrow channels that separate brain cells but cannot be directly visualized in the living brain. It is essential for normal brain function and influences many critical processes including intercellular signaling, nutrient delivery and neurotrophic effects. Significantly, the ECS also forms the final route for all drug delivery to brain cells. To develop quantitative understanding of any of these diffusion-mediated processes, essential structural parameters of the complex ECS environment must be identified and characterized. Traditional diffusion measurements, made over relatively large distances, extract two macroscopic parameters, volume fraction and tortuosity. Volume fraction is the proportion of tissue volume occupied by the ECS, and tortuosity quantifies average hindrance imposed on diffusing molecules by the complex ECS environment. The concentration of a diffusing substance is primarily influenced by volume fraction while tortuosity imposes delays in the timing. It has been taken for granted that these parameters remain constant over all diffusion distances. However, we have recently discovered that diffusion in the brain is transiently anomalous over distances of a few tens of micrometers. This means that, over this distance, the rate of diffusion depends on time and generally is faster than currently believed. To explore the phenomenon of a transiently anomalous diffusion, we introduce the concept of a Dynamic Microdomain (DM), defined as the largest volume of the brain tissue in which the anomalous diffusion is observed. The size of the DM will depend on the local structure and can change in response to various stimuli.
In Aim 1, we propose to develop a Fast Optical Tracking of Diffusion (FOTOD) method to measure DM size and analyze diffusion within it. FOTOD will be equally applicable when normal diffusion occurs in a dynamically changing ECS, e.g., during spreading depression (Aim 1) or synchronous neuronal activity (Aim 4).
Aims 2 -4 will explore several physiologically important aspects of the DM structure with this new methodology.
Aim 2 determines that structural plasticity of the astrocytic processes induced by beta2- adrenergic neuron-glia signaling represents an, as yet unrecognized, mechanism that modulates cellular communication in the visual cortex. The astrocytic processes act by altering the DM diffusion properties.
Aim 3 shows how negatively-charged perineuronal matrix nets attract polyvalent cations (e.g., calcium) but repulse polyvalent anions, thereby acting as charge discriminators within the DMs.
In Aim 4, scaling theory applied to the diffusion of flexible polymers estimates the average width of ECS pores. Very few estimates of this basic parameter exist in living brain, yet the characteristic pore width is essential for the development of drug carriers, and for any realistic model of DMs.

Public Health Relevance

Brain cells, comprising neurons and glia, are surrounded by extracellular space (ECS), a system of interconnected pores that channels chemical signals between cells and is an essential route for delivery of nutrients and drugs. This project combines experiments to measure diffusion in brain tissue with mathematical modeling to characterize the microstructure of the ECS and how it is regulated. The results will be important both for understanding how altered ECS structure in neuropathological states disrupts the chemical traffic of the brain, and for designing effective strategies to deliver drugs in patients suffering from neurological disorders and brain tumors.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS047557-10
Application #
8643295
Study Section
Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
Program Officer
Morris, Jill A
Project Start
2003-12-01
Project End
2015-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
10
Fiscal Year
2014
Total Cost
$345,418
Indirect Cost
$128,855
Name
Suny Downstate Medical Center
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
040796328
City
Brooklyn
State
NY
Country
United States
Zip Code
11203
Aoki, Chiye; Chen, Yi-Wen; Chowdhury, Tara Gunkali et al. (2017) ?4??-GABAA receptors in dorsal hippocampal CA1 of adolescent female rats traffic to the plasma membrane of dendritic spines following voluntary exercise and contribute to protection of animals from activity-based anorexia through localization at excitator J Neurosci Res :
Aoki, Chiye; Chowdhury, Tara G; Wable, Gauri S et al. (2017) Synaptic changes in the hippocampus of adolescent female rodents associated with resilience to anxiety and suppression of food restriction-evoked hyperactivity in an animal model for anorexia nervosa. Brain Res 1654:102-115
Nedelescu, Hermina; Chowdhury, Tara G; Wable, Gauri S et al. (2017) Cerebellar sub-divisions differ in exercise-induced plasticity of noradrenergic axons and in their association with resilience to activity-based anorexia. Brain Struct Funct 222:317-339
Odackal, John; Colbourn, Robert; Odackal, Namrita Jain et al. (2017) Real-time Iontophoresis with Tetramethylammonium to Quantify Volume Fraction and Tortuosity of Brain Extracellular Space. J Vis Exp :
Perkins, Katherine L; Arranz, Amaia M; Yamaguchi, Yu et al. (2017) Brain extracellular space, hyaluronan, and the prevention of epileptic seizures. Rev Neurosci 28:869-892
Chen, Yi-Wen; Actor-Engel, Hannah; Sherpa, Ang Doma et al. (2017) NR2A- and NR2B-NMDA receptors and drebrin within postsynaptic spines of the hippocampus correlate with hunger-evoked exercise. Brain Struct Funct 222:2271-2294
Shen, Hui; Sabaliauskas, Nicole; Yang, Lie et al. (2017) Role of ?4-containing GABAA receptors in limiting synaptic plasticity and spatial learning of female mice during the pubertal period. Brain Res 1654:116-122
Nicholson, Charles; Hrab?tová, Sabina (2017) Brain Extracellular Space: The Final Frontier of Neuroscience. Biophys J 113:2133-2142
Chen, Yi-Wen; Wable, Gauri Satish; Chowdhury, Tara Gunkali et al. (2016) Enlargement of Axo-Somatic Contacts Formed by GAD-Immunoreactive Axon Terminals onto Layer V Pyramidal Neurons in the Medial Prefrontal Cortex of Adolescent Female Mice Is Associated with Suppression of Food Restriction-Evoked Hyperactivity and Resilience Cereb Cortex 26:2574-89
Sherpa, Ang Doma; Xiao, Fanrong; Joseph, Neethu et al. (2016) Activation of ?-adrenergic receptors in rat visual cortex expands astrocytic processes and reduces extracellular space volume. Synapse 70:307-16

Showing the most recent 10 out of 30 publications