Activity and dendritic structural rearrangements in the mature brain

Project: Research project

Description

DESCRIPTION (provided by applicant): Mature CNS neurons have a significant intrinsic capacity for structural plasticity. This implies that they adapt to acute injury by proliferating new spines, which if consolidated, may rewire existing brain circuitry. In focal ischemia, failure of the Na+/K+ pump caused by depletion of ATP results in the anoxic depolarization (AD) with recurring AD-like peri-infarct depolarizations (PIDs) in the penumbra. The functional collapse of plasma membrane ion selectivity that drives and maintains the propagating AD, causes dramatic neuronal and glial swelling with dendritic beading and spine loss within tens of seconds. Within minutes, recurring PIDs initiate at the edge of the ischemic core, expanding neuronal damage into the penumbra during the next 1-2 days. The immediate goal of the proposed research is to address the role of these maintained depolarizations in evoking acute dendritic injury using in vitro and in vivo ischemia models. We can then test whether injury can be reduced and examine the long-term recovery of dendritic structure in vivo following focal stroke. We have discovered that dendrites become beaded and spines are lost within minutes of the Na+/K+ pump inhibition induced by ouabain or oxygen-glucose deprivation (OGD). We have shown that pump inhibition by cold, ouabain or OGD quickly elicits dendritic beading with spine loss. We have also shown that the intact neuronal membrane at normal resting potential poorly conducts water, resisting acute osmotic stress. A maintained depolarization as during stroke or cold is required to swell neurons and elicit dendritic beading and spine loss. The rapid proliferation of new spines on mature neurons during re-warming reveals an adaptive synaptogenesis in response to acute injury as dendritic structure recovers. It is unclear how long these newly spines persist or whether they are eliminated or stabilized when activated. Therefore the specific aims of this project are: 1) Investigate dynamics of AD-mediated injury and recovery of dendritic structure in acute slices. 2) Assess dynamics of dendritic injury during penumbra recruitment in vivo and during long- term recovery of synaptic circuitry post-stroke. 3) Study the ionic mechanisms underlying dendritic structural changes during the cold-induced depolarization. 4) Determine whether new spines formed on mature neurons are preserved or eliminated upon global synaptic activation. In aims 1 and 4, our synaptic studies will correlate functional data from field recordings with structural data from 2-photon laser scanning microscopy (2PLSM). In aim 2, in vivo dendritic structure during stroke in the core, penumbra and unaffected cortical regions from acute and chronic mouse models will be imaged in real time using 2PLSM. We will directly correlate injury with blood flow and with recurring depolarizations. In aim 3, 2PLSM will be correlated with intracellular recordings to examine dendritic beading and recovery in hippocampal slices. The results will address how neurons are acutely damaged, how they recover and ways to facilitate their recovery.
StatusFinished
Effective start/end date4/1/073/31/13

Funding

  • National Institutes of Health: $283,619.00
  • National Institutes of Health: $289,406.00
  • National Institutes of Health: $286,512.00
  • National Institutes of Health: $289,160.00
  • National Institutes of Health: $289,406.00

Fingerprint

Spine
Wounds and Injuries
Brain
Neurons
Stroke
Photons
Confocal Microscopy
Dendritic Spines
Ouabain
Ischemia
Oxygen
Glucose
Osmotic Pressure
Dendrites
Neuroglia
Membrane Potentials
Adenosine Triphosphate
Cell Membrane
Ions
Membranes

ASJC

  • Medicine(all)
  • Neuroscience(all)