Showing papers by "Timothy H. Murphy published in 2007"
TL;DR: In vivo two-photon imaging used to examine changes in dendritic and vascular structure in cortical regions recovering from stroke provides a structural framework for understanding functional and behavioral changes that accompany brain injury and suggest new targets that could be exploited by future therapies to rebuild and rewire neuronal circuits lost to stroke.
Abstract: Recovery of function after stroke is thought to be dependent on the reorganization of adjacent, surviving areas of the brain. Macroscopic imaging studies (functional magnetic resonance imaging, optical imaging) have shown that peri-infarct regions adopt new functional roles to compensate for damage caused by stroke. To better understand the process by which these regions reorganize, we used in vivo two-photon imaging to examine changes in dendritic and vascular structure in cortical regions recovering from stroke. In adult control mice, dendritic arbors were relatively stable with very low levels of spine turnover ( 1.5 mm). These data provide a structural framework for understanding functional and behavioral changes that accompany brain injury and suggest new targets that could be exploited by future therapies to rebuild and rewire neuronal circuits lost to stroke.
342 citations
TL;DR: In vivo two-photon Ca2+ imaging suggests that astrocytes can respond to sensory activity in a selective manner and process information on a subsecond time scale, enabling them to potentially form an active partnership with neurons for rapid regulation of microvascular tone and neuron–astrocyte network properties.
Abstract: Elevation of intracellular Ca2+ in astrocytes can influence cerebral microcirculation and modulate synaptic transmission. Recently, in vivo imaging studies identified delayed, sensory-driven Ca2+ oscillations in cortical astrocytes; however, the long latencies of these Ca2+ signals raises questions in regards to their suitability for a role in short-latency modulation of cerebral microcirculation or rapid astrocyte-to-neuron communication. Here, using in vivo two-photon Ca2+ imaging, we demonstrate that ∼5% of sulforhodamine 101-labeled astrocytes in the hindlimb area of the mouse primary somatosensory cortex exhibit short-latency (peak amplitude ∼0.5 s after stimulus onset), contralateral hindlimb-selective sensory-evoked Ca2+ signals that operate on a time scale similar to neuronal activity and correlate with the onset of the hemodynamic response as measured by intrinsic signal imaging. The kinetics of astrocyte Ca2+ transients were similar in rise and decay times to postsynaptic neuronal transients, but decayed more slowly than neuropil Ca2+ transients that presumably reflect presynaptic transients. These in vivo findings suggest that astrocytes can respond to sensory activity in a selective manner and process information on a subsecond time scale, enabling them to potentially form an active partnership with neurons for rapid regulation of microvascular tone and neuron–astrocyte network properties.
215 citations
TL;DR: The range of influence that blood flow can have on local cortical fine structure and function is defined and peri-infarct tissues can be functional within the first few hours after stroke and well positioned to aid in poststroke recovery.
Abstract: In vivo two-photon microscopy was used to image in real time dendrites and their spines in a mouse photothrombotic stroke model that reduced somatosensory cortex blood flow in discrete regions of cortical functional maps. This approach allowed us to define relationships between blood flow, cortical structure, and function on scales not previously achieved with macroscopic imaging techniques. Acute ischemic damage to dendrites was triggered within 30 min when blood flow over >0.2 mm2 of cortical surface was blocked. Rapid damage was not attributed to a subset of clotted or even leaking vessels (extravasation) alone. Assessment of stroke borders revealed a remarkably sharp transition between intact and damaged synaptic circuitry that occurred over tens of μm and was defined by a transition between flowing and blocked vessels. Although dendritic spines were normally ~13 μm from small flowing vessels, we show that intact dendritic structure can be maintained (in areas without flowing vessels) by blood flow from vessels that are on average 80 μm away. Functional imaging of intrinsic optical signals associated with activity-evoked hemodynamic responses in somatosensory cortex indicated that sensory-induced changes in signal were blocked in areas with damaged dendrites, but were present ~400 μm away from the border of dendritic damage. These results define the range of influence that blood flow can have on local cortical fine structure and function, as well as to demonstrate that peri-infarct tissues can be functional within the first few hours after stroke and well positioned to aid in poststroke recovery.
198 citations
TL;DR: The data suggest that the axonal and dendritic circuitry of neurons located 300 μm outside of an ischemic zone can be relatively free of damage or commitment to cell death suggesting that they may be in an ideal position to contribute to functional recovery.
Abstract: We have evaluated the spatial relationship between clotted vasculature and the structural integrity of layer V cortical neurons in YFP (yellow fluorescent protein)-H transgenic mice 2 to 10 h after photothrombotic stroke. Fortuitously, ischemic zones could be finely mapped about dysmorphic YFP labeled axons and dendrites using histology since texas-red dextran used to assess blood flow in vivo was trapped within fixed clotted vessels. Ischemic damage to layer V neurons located at the border of ischemia was contained within apical tuft spiny dendritic structures and did not propagate to spines on the more proximal region of the apical dendrite. The lateral spread of dendritic damage decayed sharply with distance from the edge of ischemia (50% reduction in beaded dendrites within ~ 100 μm) and increased with time up to 6 h after stroke but not thereafter. Axonal damage also increased with time but extended further laterally than dendritic damage, up to 500 μm from the stroke core. Apoptotic and necrotic cel...
75 citations
TL;DR: Current-clamp recordings confirmed a direct depolarizing action of nicotine that could dampen eIPSC activity leading to a switch to striatal inhibitory synaptic transmission mediated by tonic mIPSCs.
Abstract: Stimulation of presynaptic nicotinic acetylcholine receptors (nAChRs) increases the frequency of miniature excitatory synaptic activity (mEPSCs) to a point where they can promote cell firing in hip...
24 citations
TL;DR: While Nrf2 is a transcriptional regulator of xCT and capable of protecting cells from oxidative stress, this role can be partially compensated by other mechanisms and methamphetamine-induced oxidative stress and dopamine toxicity does not significantly involve NRF2.
22 citations
TL;DR: In vivo observations indicate that a high level of cellular proliferation in the adult brain persists even in the absence of functional xCT, and demonstrates that xCT expression plays a role in regulating cellulariferation in the DG, but not the SVZ of adult mice.
18 citations
TL;DR: Heterogeneity in release rates between synapses suggests that similar patterns of presynaptic action potentials could trigger different forms of plasticity at individual synapses.
Abstract: To understand how information is coded at single hippocampal synapses during high-frequency activity, we imaged NMDA receptor-mediated Ca2+ responses in spines of CA1 neurons using two-photon microscopy. Although discrete quantal events were not readily apparent during continuous theta-burst stimulation (TBS), we found that the steady-state dendritic Ca2+ response was spatially restricted (half-width < 1 μm), voltage dependent and sensitive to MK-801, indicating that that it was mediated by activation of NMDA receptors at single synapses. Partial antagonism of NMDA receptors caused a similar reduction of NMDA EPSCs (measured at the soma) and local dendritic Ca2+ signals, suggesting that, like EPSCs, the steady-state Ca2+ signal was made up of a linear addition of quantal events. Statistical analyses of the steady-response suggested that the quantal size did not change dramatically during TBS. Deconvolution of TBS-evoked Ca2+ responses revealed a heterogeneous population of synapses differing in their capacity to signal high-frequency information, with an average effective steady-state release rate of ∼2.6 vesicles synapse−1 s−1. To assess how the optically determined release rates compare with population measures we analysed the rate of decay of peak EPSCs during train stimulation. From these studies, we estimated a unitary vesicular replenishment rate of 0.02 s−1, which corresponds to an average release rate of ∼0.8–2 vesicles s−1 at individual synapses. Additionally, extracellular recordings from single Schaffer collaterals revealed that spikes propagate reliably during TBS. Hence, during high-frequency activity, Schaffer collaterals conduct spikes with high fidelity, but release quanta with relatively lower efficiency, leaving NMDA receptor function largely intact and synapse specific. Heterogeneity in release rates between synapses suggests that similar patterns of presynaptic action potentials could trigger different forms of plasticity at individual synapses.
10 citations