Candice E. Van Skike, Stacy A. Hussong, Stephen F. Hernandez, Andy Q. Banh, Nicholas DeRosa et al. (see pages [4305–4320][1]) Disruption of cerebral blood flow and its regulation by neural activity (neurovascular coupling) occur early in Alzheimer's disease (AD), often before other symptoms

The brain functions through coordinated activity among distributed regions. Wide-field calcium imaging, combined with improved genetically encoded calcium indicators, allows sufficient signal-to-noise ratio and spatiotemporal resolution to afford a unique opportunity to capture cortex-wide dynamics on a moment-by-moment basis in behaving animals. Recent applications of this approach have been uncovering cortical dynamics at unprecedented scales during various cognitive processes, ranging from relatively simple sensorimotor integration to more complex decision-making tasks. In this review, we will highlight recent scientific advances enabled by wide-field calcium imaging in behaving mice. We then summarize several technical considerations and future opportunities for wide-field imaging to uncover large-scale circuit dynamics.

A long-held tenet in the pharmacology of drug abuse is that, despite marked differences in cellular targets, addictive drugs reinforce drug taking by increasing dopamine (DA) transmission in the Nucleus accumbens (NAc; [Di Chiara and Imperato, 1988][1]). Opioid-evoked DA release in the NAc has been

Vascular dysfunction is a universal feature of aging and decreased cerebral blood flow has been identified as an early event in the pathogenesis of Alzheimer's disease (AD). Cerebrovascular dysfunction in AD includes deficits in neurovascular coupling (NVC), a mechanism that ensures rapid delivery of energy substrates to active neurons through the blood supply. The mechanisms underlying NVC impairment in AD, however, are not well understood. We have previously shown that mechanistic/mammalian target of rapamycin (mTOR) drives cerebrovascular dysfunction in models of AD by reducing the activity of endothelial nitric oxide synthase (eNOS), and that attenuation of mTOR activity with rapamycin is sufficient to restore eNOS-dependent cerebrovascular function. Here we show mTOR drives NVC impairments in an AD model through the inhibition of neuronal NOS (nNOS)- and non-NOS-dependent components of NVC, and that mTOR attenuation with rapamycin is sufficient to restore NVC and even enhance it above WT responses. Re...

Oligodendrocyte progenitor cells (OPC) are specified from discrete precursor populations during gliogenesis and migrate extensively from their origins, ultimately distributing throughout the brain and spinal cord during early development. Subsequently, a subset of OPCs differentiates into mature oligodendrocytes, which myelinate axons. This process is necessary for efficient neuronal signaling and organism survival. Previous studies have identified several factors that influence OPC development, including excitatory glutamatergic synapses that form between neurons and OPCs during myelination. However, little is known about how glutamate signaling affects OPC migration prior to myelination. In this study, we use in vivo, time-lapse imaging in zebrafish in conjunction with genetic and pharmacological perturbation to investigate OPC migration and myelination when the GluR4A ionotropic glutamate receptor subunit is disrupted. In our studies, we observed that gria4a mutant embryos and larvae displayed abnormal ...

Presynaptic active zone proteins couple calcium influx with synaptic vesicle exocytosis. However, the control of presynaptic calcium channel localization by active zone proteins is not completely understood. In a C. elegans forward genetic screen, we find that UNC-10/RIM (Rab3-interacting molecule) and SYD-2/Liprin-α regulate presynaptic localization of UNC-2, the CaV2 channel ortholog. We further quantitatively analyzed live animals using endogenously GFP-tagged UNC-2 and active zone components. Consistent with the interaction between RIM and CaV2 in mammals, the intensity and number of UNC-2 channel puncta at presynaptic terminals were greatly reduced in unc-10 mutant animals. To understand how SYD-2 regulates presynaptic UNC-2 channel localization, we analyzed presynaptic localization of endogenous SYD-2, UNC-10, RIMB-1/RIM-BP (RIM binding protein), and ELKS-1. Our analysis revealed that while SYD-2 is the most critical for active zone assembly, loss of SYD-2 function does not completely abolish presyna...

Cognitive dysfunction, is among the hallmark symptoms of Neurofibromatosis 1, and accordingly, loss of the Drosophila melanogaster ortholog of Neurofibromin 1 (dNf1), precipitates associative learning deficits. However, the affected circuitry in the adult CNS remained unclear and the compromised mechanisms debatable. Although the main evolutionarily conserved function attributed to Nf1 is to inactivate Ras, decreased cAMP signalling upon its loss has been thought to underlie impaired learning. Using mixed sex populations, we determine that dNf1 loss results in excess GABAergic signaling to the central for associative learning Mushroom Body (MB) neurons, apparently suppressing learning. dNf1 is necessary and sufficient for learning within these non-MB neurons, as a dAlk and Ras1-dependent, but PKA-independent modulator of GABAergic neurotransmission. Surprisingly, we also uncovered and discuss a postsynaptic Ras1-dependent, but dNf1-independnet signaling within the MBs that apparently responds to presynapti...

Mutations on γ-secretase subunits are associated with neurological diseases. Whereas the role of γ-secretase in neurogenesis has been intensively studied, little is known about its role in astrogliogenesis. Recent evidence has demonstrated that astrocytes can be generated from oligodendrocyte (OL) precursor cells (OPCs). However, it is not well understood what mechanism may control OPCs to differentiate into astrocytes. To address the above questions, we generated two independent lines of OL lineage specific presenilin enhancer 2 ( Pen-2 ) conditional knockout (cKO) mice. Both male and female mice were used. Here we demonstrate that conditional inactivation of Pen-2 mediated by Olig1-Cre or NG2-CreERT2 causes enhanced generation of astrocytes. Lineage-tracing experiments indicate that abnormally generated astrocytes are derived from Cre-expressing OPCs in the central nervous system (CNS) in Pen-2 cKO mice. Mechanistic analysis reveals that deletion of Pen-2 inhibits the Notch signaling to up-regulate signa...

Activating transcription factor 4 (ATF4/CREB2), in addition to its well-studied role in stress responses, is proposed to play important physiologic functions in regulating learning and memory. However, the nature of these functions has not been well defined and is subject to apparently disparate views. Here, we provide evidence that ATF4 is a regulator of excitability during synaptic plasticity. We evaluated ATF4's role in mature hippocampal cultures subjected to a brief chemical-LTP (cLTP) induction protocol that results in changes in mEPSC properties and synaptic AMPA receptor density one hour later, with return to baseline by 24 hours. We find that ATF4 protein, but not its mRNA, is rapidly depleted by about 50% in response to cLTP induction via NMDA receptor activation. Depletion is detectable in dendrites within 15 min and in cell bodies by 1 hour and returns to baseline by 8 hours. Such changes correlate with a parallel depletion of phospho-eIF2a, suggesting that ATF4 loss is driven by decreased tran...

Focused attention to spontaneous sensations is a dynamic process that demands interoceptive abilities. Failure to control it has been linked to neuropsychiatric disorders like illness-anxiety disorder. Regulatory strategies, such as focused attention meditation, may enhance the ability to control focused attention particularly to body sensations, which can be reflected on functional neuroanatomy. The functional connectivity (FC) related to focused attention has been described, however, the dynamic brain organization associated to this process and the differences to the resting state remains to be studied. To quantify the cerebral dynamic counterpart of focused attention to interoception, we examined fifteen experienced meditators while performing a 20-minute attentional task to spontaneous sensations. Subjects underwent three scanning sessions obtaining a resting-state scan before and after the task. Sliding window dynamic functional connectivity and k-means clustering identified five recurrent FC patterns...