Selective representations of texture and motion in mouse higher visual areas.

The mouse visual cortex contains interconnected higher visual areas, but their functional specializations are unclear. Here, we used a data-driven approach to examine the representations of complex visual stimuli by L2/3 neurons across mouse higher visual areas, measured using large-field-of-view two-photon calcium imaging. Using specialized stimuli, we found higher fidelity representations of texture in area LM, compared to area AL. Complementarily, we found higher fidelity representations of motion in area AL, compared to area LM. We also observed this segregation of information in response to naturalistic videos. Finally, we explored how receptive field models of visual cortical neurons could produce the segregated representations of texture and motion we observed. These selective representations could aid in behaviors such as visually guided navigation.

Deficits in higher visual area representations in a mouse model of Angelman syndrome.

BACKGROUND: Sensory processing deficits are common in individuals with neurodevelopmental disorders. One hypothesis is that deficits may be more detectable in downstream, "higher" sensory areas. A mouse model of Angelman syndrome (AS), which lacks expression of the maternally inherited Ube3a allele, has deficits in synaptic function and experience-dependent plasticity in the primary visual cortex. Thus, we hypothesized that AS model mice have deficits in visually driven neuronal responsiveness in downstream higher visual areas (HVAs). METHODS: Here, we used intrinsic signal optical imaging and two-photon calcium imaging to map visually evoked neuronal activity in the primary visual cortex and HVAs in response to an array of stimuli. RESULTS: We found a highly specific deficit in HVAs. Drifting gratings that changed speed caused a strong response in HVAs in wildtype mice, but this was not observed in littermate AS model mice. Further investigation with two-photon calcium imaging revealed the effect to be largely driven by aberrant responses of inhibitory interneurons, suggesting a cellular basis for higher level, stimulus-selective cortical dysfunction in AS. CONCLUSION: Assaying downstream, or "higher" circuitry may provide a more sensitive measure for circuit dysfunction in mouse models of neurodevelopmental disorders. TRIAL REGISTRATION: Not applicable.

Traumatic Brain Injury Induces Alterations in Cortical Glutamate Uptake without a Reduction in Glutamate Transporter-1 Protein Expression.

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.

Glutamate Neurotransmission in Rodent Models of Traumatic Brain Injury.

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.

Interaction of Intrinsic and Synaptic Currents Mediate Network Resonance Driven by Layer V Pyramidal Cells.

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.