Traumatic brain injury (TBI) is a leading cause of death and disability in people younger than 45 and is a significant public health concern. In addition to primary mechanical damage to cells and tissue, TBI involves additional molecular mechanisms of injury, termed secondary injury, that continue to evolve over hours, days, weeks, and beyond. The trajectory of recovery after TBI is highly unpredictable and in many cases results in chronic cognitive and behavioral changes. Acutely after TBI, there is an unregulated release of glutamate that cannot be buffered or cleared effectively, resulting in damaging levels of glutamate in the extracellular space. This initial loss of glutamate homeostasis may initiate additional changes in glutamate regulation. The excitatory amino acid transporters (EAATs) are expressed on both neurons and glia and are the principal mechanism for maintaining extracellular glutamate levels. Diffusion of glutamate outside the synapse due to impaired uptake may lead to increased extrasynaptic glutamate signaling, secondary injury through activation of cell death pathways, and loss of fidelity and specificity of synaptic transmission. Coordination of glutamate release and uptake is critical to regulating synaptic strength, long-term potentiation and depression, and cognitive processes. In this review, we will discuss dysregulation of extracellular glutamate and glutamate uptake in the acute stage of TBI and how failure to resolve acute disruptions in glutamate homeostatic mechanisms may play a causal role in chronic cognitive symptoms after TBI.
We hypothesize that the primary mechanism for removal of glutamate from the extracellular space is altered after traumatic brain injury (TBI). To evaluate this hypothesis, we initiated TBI in adult male rats using a 2.0 atm lateral fluid percussion injury (LFPI) model. In the ipsilateral cortex and hippocampus, we found no differences in expression of the primary glutamate transporter in the brain (GLT-1) 24 h after TBI. In contrast, we found a decrease in glutamate uptake in the cortex, but not the hippocampus, 24 h after injury. Because glutamate uptake is potently regulated by protein kinases, we assessed global serine-threonine protein kinase activity using a kinome array platform. Twenty-five kinome array peptide substrates were differentially phoshorylated between LFPI and controls in the cortex, whereas 19 peptide substrates were differentially phosphorylated in the hippocampus (fold change ≥ ± 1.15). We identified several kinases as likely to be involved in acute TBI, including protein kinase B (Akt) and protein kinase C (PKC), which are well-characterized modulators of GLT-1. Exploratory studies using an inhibitor of Akt suggest selective activation of kinases in LFPI versus controls. Ingenuity pathway analyses of implicated kinases from our network model found apoptosis and cell death pathways as top functions in acute LFPI. Taken together, our data suggest diminished activity of glutamate transporters in the prefrontal cortex, with no changes in protein expression of the primary glutamate transporter GLT-1, and global alterations in signaling networks that include serine-threonine kinases that are known modulators of glutamate transport activity.
Cortical oscillations modulate cellular excitability and facilitate neuronal communication and information processing. Layer 5 pyramidal cells (L5 PYs) drive low-frequency oscillations (<4 Hz) in neocortical networks in vivo. In vitro, individual L5 PYs exhibit subthreshold resonance in the theta band (4-8 Hz). This bandpass filtering of periodic input is mediated by h-current (Ih) and m-current (IM) that selectively suppress low-frequency input. It has remained unclear how these intrinsic properties of cells contribute to the emergent, network oscillation dynamics. To begin to close this gap, we studied the link between cellular and network mechanisms of network resonance driven by L5 PYs. We performed multielectrode array recordings of network activity in slices of medial prefrontal cortex from the Thy1-ChR2-eYFP line and activated the network by temporally patterned optogenetic suprathreshold stimulation. Networks driven by stimulation of L5 PYs exhibited resonance in the theta band. We found that Ih and IM play a role in resonant suprathreshold network response to depolarizing stimuli. The action of Ih in mediating resonance was dependent on synaptic transmission while that of IM was not. These results demonstrate how synergistic interaction of synaptic and intrinsic ion channels contribute to the response of networks driven by L5 PYs.
11Neural circuitry represents sensory input with patterns of spiking activity. Across brain regions, initial 12representations are transformed to ultimately drive adaptive behavior. In mammalian neocortex, visual 13 information is processed by primary visual cortex (V1) and multiple higher visual areas (HVAs). The 14interconnections of these brain regions, over which transformations can occur, span millimeters or more. 15Shared variability in spiking responses between neurons, called "noise correlations" (NCs), can be due 16to shared input and/or direct or indirect connectivity. Thus, NCs provide insight into the functional 17 connectivity of neuronal circuits. In this study, we used subcellular resolution, mesoscale field-of-view 18 two-photon calcium imaging to systematically characterize the NCs for pairs of layer 2/3 neurons across 19 V1 and four HVAs (areas LM, LI, AL and PM) of mice. The average NCs for pairs of neurons within or 20 across cortical areas were orders of magnitude larger than trial-shuffled control values. We characterized 21 the modulation of NCs by neuron distance, tuning similarity, receptive field overlap, and stimulus type 22 over millimeter scale distances in mouse visual cortex, within and across V1 and multiple HVAs. NCs 23were positively correlated with shared tuning and receptive field overlap, even across cortical areas and 24 millimeter length scales. We compared the structure of these NCs to that of hypothetical networks to 25 determine what network types can account for the results. We found that to reproduce the NC networks, 26 neuron connectivity was regulated by both feature similarities and hub mechanism. Overall, these results 27revealed principles for the functional organization and correlation structure at the individual neuron level 28 across multiple cortical areas, which can inform and constrain computational theories of cortical networks. 30Navigating the environment, detecting predators, and recognizing mates are natural behaviors of 31 mammals that can depend upon sophisticated visual perception. Visual information is encoded and 32 abstracted through multiple interconnected brain areas, which span millimeters in the mouse 1 . These 33interconnections, both within and between brain areas, are critical components underlying brain functions. 34Anatomical tracing studies of flies 2 and mice 3 , have provided insights into basic neuronal wiring principles. 35However, anatomical connectivity is insufficient for understanding the circuit interactions of an active 36 brain, and the relationships between function and connectivity. Thus, in this study we investigated the 37 functional circuit connectivity structure at millimeter scale. 38Neuronal responses vary on nominally identical trials. The trial-to-trial variability of responses is 39 correlated in a neuronal population. This shared variability between pairs of neurons can be quantified, 40and is called noise correlation (NC) 4 . The structure of NCs is rooted in the architecture of the neuronal 41circuit, e.g., shared...
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