Corey Acker - Academia.edu (original) (raw)

Papers by Corey Acker

Biophysical Journal, 2014

Journal of computational neuroscience

Behavior of a network of neurons is closely tied to the properties of the individual neurons. We ... more Behavior of a network of neurons is closely tied to the properties of the individual neurons. We study this relationship in models of layer II stellate cells (SCs) of the medial entorhinal cortex. SCs are thought to contribute to the mammalian theta rhythm (4-12 Hz), and are notable for the slow ionic conductances that constrain them to fire at rates within this frequency range. We apply "spike time response" (STR) methods, in which the effects of synaptic perturbations on the timing of subsequent spikes are used to predict how these neurons may synchronize at theta frequencies. Predictions from STR methods are verified using network simulations. Slow conductances often make small inputs "effectively large"; we suggest that this is due to reduced attractiveness or stability of the spiking limit cycle. When inputs are (effectively) large, changes in firing times depend nonlinearly on synaptic strength. One consequence of nonlinearity is to make a periodically firi...

In this protocol, we describe the procedures we have developed to optimize the performance of vol... more In this protocol, we describe the procedures we have developed to optimize the performance of voltage-sensitive dyes for recording changes in neuronal electrical activity. We emphasize our experience in finding the best dye conditions for recording backpropagating action potentials from individual dendritic spines in a neuron within a brain slice. We fully describe procedures for loading the dye through a patch pipette and for finding excitation and emission wavelengths for the best sensitivity of the fluorescence signal to membrane voltage. Many of these approaches can be adapted to in vivo preparations and to experiments on mapping brain activity via optical recording.

Frontiers in Systems Neuroscience, 2009

Proceedings of the National Academy of Sciences, 2005

Repeated induction of pre- and postsynaptic action potentials (APs) at a fixed time difference le... more Repeated induction of pre- and postsynaptic action potentials (APs) at a fixed time difference leads to long-term potentiation (LTP) or long-term depression (LTD) of the synapse, depending on the temporal order of pre- and postsynaptic activity. This phenomenon of spike-timing-dependent plasticity (STDP) is believed to arise by nonlinear processes that lead to larger calcium transients (and thus LTP) when presynaptic APs precede postsynaptic APs and smaller calcium transients (and thus LTD) when postsynaptic APs precede presynaptic APs. In contrast to predictions from such calcium-peak-detector models, we show that constitutively or artificially broadened APs in layer II/III pyramidal cells of entorhinal cortex (EC) lead to an increase in the dendritic calcium transient and shift the balance of STDP toward LTD. STDP in entorhinal pyramidal cells is NMDA-receptor-dependent and modulated by the Ca(V)1Ca(2+) channel-blocker nifedipine. Results are consistent with an elaboration of the calcium-peak-detector model in which downstream signals from voltage-dependent Ca(2+) channels suppress LTP relative to LTD. Our results suggest that modulation of AP width is a potent way to adjust the rules of synaptic plasticity in the EC.

Journal of Neurophysiology, 2005

Slow and fast inhibition and an h-current interact to create a theta rhythm in a model of CA1 int... more Slow and fast inhibition and an h-current interact to create a theta rhythm in a model of CA1 interneuron network. . The orienslacunosum moleculare (O-LM) subtype of interneuron is a key component in the formation of the theta rhythm (8 -12 Hz) in the hippocampus. It is known that the CA1 region of the hippocampus can produce theta rhythms in vitro with all ionotropic excitation blocked, but the mechanisms by which this rhythmicity happens were previously unknown. Here we present a model suggesting that individual O-LM cells, by themselves, are capable of producing a single-cell theta-frequency firing, but coupled O-LM cells are not capable of producing a coherent population theta. By including in the model fast-spiking (FS) interneurons, which give rise to IPSPs that decay faster than those of the O-LM cells, coherent theta rhythms are produced. The inhibition to O-LM cells from the FS cells synchronizes the O-LM cells, but only when the FS cells themselves fire at a theta frequency. Reciprocal connections from the O-LM cells to the FS cells serve to parse the FS cell firing into theta bursts, which can then synchronize the O-LM cells. A component of the model O-LM cell critical to the synchronization mechanism is the hyperpolarization-activated h-current. The model can robustly reproduce relative phases of theta frequency activity in O-LM and FS cells. Acker CD, Kopell N, and White JA. Synchronization of strongly coupled excitatory neurons: relating network behavior to biophysics. J Comput Neurosci 15: 71-90, 2003. Alagarsamy S, Marino MJ, Rouse ST, Gereau RW IV, Heinemann SF, and Conn PJ. Activation of NMDA receptors reverses desensitization of mGluR5 in native and recombinant systems. Nat Neurosci 2: 234 -240, 1999b. Alagarsamy S, Rouse ST, Gereau RW IV, Heinemann SF, Smith Y, and Conn PJ. Activation of N-methyl-D-aspartate receptors reverses desensitization of metabotropic glutamate receptor, mGluR5, in native and recombinant systems. Ann NY Acad Sci 868: 526 -530, 1999a. Ali A and Thomson A. Facilitating pyramid to horizontal oriensalveus interneurone inputs: dual intracellular recordings in slices of rat hippocampus. J Physiol 507: 185-199, 1998. Alonso AA and Llinás RR. Subthreshold Na ϩ -dependent theta like rhythmicity in stellate cells of entorhinal cortex layer II. Nature 342: 175-177, 1989.

Journal of Neurophysiology, 2004

Understanding the mechanistic bases of neuronal synchronization is a current challenge in quantit... more Understanding the mechanistic bases of neuronal synchronization is a current challenge in quantitative neuroscience. We studied this problem in two putative cellular pacemakers of the mammalian hippocampal theta rhythm: glutamatergic stellate cells (SCs) of the medial entorhinal cortex and GABAergic oriens-lacunosum-moleculare (O-LM) interneurons of hippocampal region CA1. We used two experimental methods. First, we measured changes in spike timing induced by artificial synaptic inputs applied to individual neurons. We then measured responses of free-running hybrid neuronal networks, consisting of biological neurons coupled (via dynamic clamp) to biological or virtual counterparts. Results from the single-cell experiments predicted network behaviors well and are compatible with previous model-based predictions of how specific membrane mechanisms give rise to empirically measured synchronization behavior. Both cell types phase lock stably when connected via homogeneous excitatory-excitatory (E-E) or inhibitory-inhibitory (I-I) connections. Phase-locked firing is consistently synchronous for either cell type with E-E connections and nearly anti-synchronous with I-I connections. With heterogeneous connections (e.g., excitatory-inhibitory, as might be expected if members of a given population had heterogeneous connections involving intermediate interneurons), networks often settled into phase locking that was either stable or unstable, depending on the order of firing of the two cells in the hybrid network. Our results imply that excitatory SCs, but not inhibitory O-LM interneurons, are capable of synchronizing in phase via monosynaptic mutual connections of the biologically appropriate polarity. Results are largely independent of synaptic strength and synaptic kinetics, implying that our conclusions are robust and largely unaffected by synaptic plasticity.

Journal of Neurophysiology, 2009

Acker CD, Antic SD. Quantitative assessment of the distributions of membrane conductances involve... more Acker CD, Antic SD. Quantitative assessment of the distributions of membrane conductances involved in action potential backpropagation along basal dendrites. drites of prefrontal cortical neurons receive strong synaptic drive from recurrent excitatory synaptic inputs. Synaptic integration within basal dendrites is therefore likely to play an important role in cortical information processing. Both synaptic integration and synaptic plasticity depend crucially on dendritic membrane excitability and the backpropagation of action potentials. We carried out multisite voltage-sensitive dye imaging of membrane potential transients from thin basal branches of prefrontal cortical pyramidal neurons before and after application of channel blockers. We found that backpropagating action potentials (bAPs) are predominantly controlled by voltagegated sodium and A-type potassium channels. In contrast, pharmacologically blocking the delayed rectifier potassium, voltage-gated calcium, or I h conductance had little effect on dendritic AP propagation. Optically recorded bAP waveforms were quantified and multicompartmental modeling was used to link the observed behavior with the underlying biophysical properties. The best-fit model included a nonuniform sodium channel distribution with decreasing conductance with distance from the soma, together with a nonuniform (increasing) A-type potassium conductance. AP amplitudes decline with distance in this model, but to a lesser extent than previously thought. We used this model to explore the mechanisms underlying two sets of published data involving high-frequency trains of APs and the local generation of sodium spikelets. We also explored the conditions under which I A down-regulation would produce branch strength potentiation in the proposed model. Finally, we discuss the hypothesis that a fraction of basal branches may have different membrane properties compared with sister branches in the same dendritic tree.

Journal of Computational Neuroscience, 2007

Dendrites of CA1 pyramidal cells of the hippocampus, along with those of a wide range of other ce... more Dendrites of CA1 pyramidal cells of the hippocampus, along with those of a wide range of other cell types, support active backpropagation of axonal action potentials. Consistent with previous work, recent experiments demonstrating that properties of synaptic plasticity are different for distal synapses, suggest an important functional role of bAPs, which are known to be prone to failure in distal locations. Using conductance-based models of CA1 pyramidal cells, we show that underlying "traveling wave attractors" control action potential propagation in the apical dendrites. By computing these attractors, we dissect and quantify the effects of I A channels and dendritic morphology on bAP amplitudes. We find that non-uniform activation properties of I A can lead to backpropagation failure similar to that observed experimentally in these cells. Amplitude of forward propagation of dendritic spikes also depends strongly on the activation dynamics of I A . I A channel properties also influence transients at dendritic branch points and whether or not propagation failure results. The branching pattern in the distal apical dendrites, combined with I A channel properties in this region, ensure propagation failure in the apical tuft for a large range of I A conductance densities. At the same time, these same properties ensure failure of forward propagating dendritic spikes initiated in the distal tuft in the absence of some form of cooperativity of synaptic activation.

Journal of Computational Neuroscience, 2005

Oscillations of large populations of neurons are thought to be important in the normal functionin... more Oscillations of large populations of neurons are thought to be important in the normal functioning of the brain. We have used phase response curve (PRC) methods to characterize the dynamics of single neurons and predict population dynamics. Our past experimental work was limited to special circumstances (e.g., 2-cell networks of periodically firing neurons). Here, we explore the feasibility of extending our methods to predict the synchronization properties of stellate cells (SCs) in the rat entorhinal cortex under broader conditions. In particular, we test the hypothesis that PRCs in SCs scale linearly with changes in synaptic amplitude, and measure how well responses to Poisson process-driven inputs can be predicted in terms of PRCs. Although we see nonlinear responses to excitatory and inhibitory inputs, we find that models based on weak coupling account for scaling and Poisson process-driven inputs reasonably accurately.

Biophysical Journal, 2012

in physiological and pathological processes and thus central for the function of biological syste... more in physiological and pathological processes and thus central for the function of biological systems. We describe a fast and reliable ratiometric Fluorescence Lifetime Imaging Microscopy (rmFLIM) approach to analyze the distribution of protein-ligand complexes in the cellular context. 1 Binding of the fluorescently labeled antagonist naloxone to the G-protein coupled m-opioid receptor is used as an example. To show the broad applicability of the rmFLIM method we extended this approach to investigate the distribution of polymer-based nanocarriers in histological liver sections. Many early trials at protein crystallization produce large amounts of subdiffraction limited crystals. These nanocrystalline showers are challenging to quantitatively characterize by conventional optical methods; however, they can offer important indicators for improving crystallization conditions. Additionally, the advent and availability of ultrafast X-ray free-electron lasers now allows single-pulse diffraction from individual protein nanocrystals for structure determination. However, these and other applications of nanocrystals currently suffer major bottlenecks in sample characterization, limiting their broader utility. Second harmonic generation correlation spectroscopy (SHG-CS) is being developed to address this key characterization need. Under tight focus and high laser intensity, highly-ordered (crystalline) material lacking inversion symmetry; including the vast majority of protein crystals but not simple salt crystals, amorphous protein, solvents, etc.; allow for second harmonic generation, the frequency doubling of light. This provides a way to selectively track crystalline protein particles in solution. The size of the particles can be determined by taking advantage of the fact that the particles diffuse through solution. The amount of

Biophysical Journal, 2013

Fluorescence imaging provides both spatial and temporal information about target molecules in bio... more Fluorescence imaging provides both spatial and temporal information about target molecules in biological systems. We have proposed to use imaging as a detection technique in microparticle based immunoassays. It has advantage over traditional approaches which measure only total signal but do not make use of the spatial or temporal information embedded in the system. The method can be readily adapted for quick assay prototyping and high throughput screening on any conventional fluorescence imaging system. In microparticle immunoassays, analytes are captured with antibody coated microparticles and subsequently detected using second antibody labeled with a reporter group. In HDIA, fluorescence images of the microparticles are examined pixel-by-pixel to extract binding information only from the microparticles, thus minimizing irrelevant signals from solution and vessel surfaces. Our model systems include sandwich based Troponin and Bcl-xl (B-cell lymphoma-extra large) protein assays, as well as homogeneous competitive Methotrexate immunoassay. Performance of the HDIA is dominated by binding kinetics of the microparticles. Depending on the microparticle number, concentration of the binding sites on microparticles, sample volume, sample concentration and the geometry of the reaction vessel, the binding kinetics can be either reaction limited or diffusion limited. We will present the effects of these factors on the binding kinetics of HDIA. Dendritic spines are the initial site of the processing of information carried by excitatory network activity. Spine morphology often includes a narrow neck, which is known to isolate the biochemical signaling components within the spine from the dendritic branch. To what degree spines are isolated electrically and how local excitatory postsynaptic potentials (EPSPs) behave is still not fully understood. It is known, however, that the larger the electrical isolation, the larger the amplitude of membrane potential changes, which may have a significant impact on signaling mechanisms within the spine responsible for important processes such as synaptic plasticity. We are addressing this question using 2-photon imaging of voltage sensitive dyes along with synaptic activation via glutamate uncaging in acute brain slices. using a custom microscope we can control the positions of both a recording laser (fixed at the center of a spine) and the uncaging pulse directed at the desired uncaging position just off the spine. The amplitudes of the optical signals in the spine are calibrated using backpropagating action potential waveforms, which, as previously described, is consistent across spines of different sizes and shapes. Uncaging-evoked EPSP amplitudes are typically 10mV-20mV, which are highly attenuated upon reaching the soma, where they typically appear 20 fold smaller in amplitude. Additionally, EPSP dynamics within the spine are typically much faster in the spine, with half-widths around 5-10ms, compared to the same EPSPs measured at the soma, which are typically 50-100ms. The observed attenuation of EPSP amplitudes and increase in duration were used to fit a biophysical, NEURON-based model, in order to explore the role of the spine geometry. NIH grants R01

Biophysical Journal, 2010

Biophysical Journal, 2011

We report sensitive recording of membrane potential in single dendritic spines in cortical neuron... more We report sensitive recording of membrane potential in single dendritic spines in cortical neurons within a brain slice using two-photon excitation and a new, fluorinated, intracellularly loaded organic dye, di-2-AN(F)EPPTEA. With a two-photon excitation wavelength of 1060 nm, we achieve voltage sensitivity of >16% change in fluorescence per 100 mV. By targeting single spines in single-voxel recordings, we attain excellent single/noise quality, with back-propagating action potentials (bAPs) visible in single sweeps while recording at 10 kHz. This recording rate allows us to reliably assess fast bAP dynamics on single sweeps including bAP rise times of 0.5 ms. The amplitude and propagation delays of the bAPs are similar among different spines located within the same dendritic region, and this is true despite large differences in spine size. The interregion differences in bAP waveforms in spines vary in relation to their distance from the soma and the caliber of their parent dendrites.

Proceedings of the National Academy of Sciences, 2012

Optical recording of membrane potential permits spatially resolved measurement of electrical acti... more Optical recording of membrane potential permits spatially resolved measurement of electrical activity in subcellular regions of single cells, which would be inaccessible to electrodes, and imaging of spatiotemporal patterns of action potential propagation in excitable tissues, such as the brain or heart. However, the available voltage-sensitive dyes (VSDs) are not always spectrally compatible with newly available optical technologies for sensing or manipulating the physiological state of a system. Here, we describe a series of 19 fluorinated VSDs based on the hemicyanine class of chromophores. Strategic placement of the fluorine atoms on the chromophores can result in either blue or red shifts in the absorbance and emission spectra. The range of one-photon excitation wavelengths afforded by these new VSDs spans 440-670 nm; the twophoton excitation range is 900-1,340 nm. The emission of each VSD is shifted by at least 100 nm to the red of its one-photon excitation spectrum. The set of VSDs, thus, affords an extended toolkit for optical recording to match a broad range of experimental requirements. We show the sensitivity to voltage and the photostability of the new VSDs in a series of experimental preparations ranging in scale from single dendritic spines to whole heart. Among the advances shown in these applications are simultaneous recording of voltage and calcium in single dendritic spines and optical electrophysiology recordings using two-photon excitation above 1,100 nm. fluorescence | microscopy O ptical recording techniques provide powerful tools for neurobiologists (1) and cardiac physiologists (2) to study detailed patterns of electrical activity over time and space in cells, tissues, and organs. Rational design methods, based on molecular orbital calculations of the dye chromophores and characterization of their binding and orientations in membranes (3-5), were used to engineer dye structures. The general class of dye chromophores called hemicyanine (also referred to as styryl dyes) has emerged from this effort as a good foundation for voltage-sensitive dyes (VSDs), because they exhibit electrochromism. This mechanism, also referred to as the molecular Stark effect, involves the differential interaction of the electric field in the membrane with the ground and excited states of the dye chromophore. Several important hemicyanine dyes were produced over the years, including di-4-ANEPPS (6, 7), di-8-ANEPPS (8), di-2-ANEPEQ (also known as JPW-1114) (9, 10), RH-421 and RH-795 (11), ANNINE-6 and ANNINE-6+ (12, 13), di-3-ANEPPDHQ (14, 15), di-4-ANBDQBS, and di-4-ANBDQPQ (16, 17). Because the electrochromic mechanism is a direct interaction of the electric field with the chromophore and does not require any movement of the dye molecule, all of these dyes provide rapid absorbance and fluorescence responses to membrane potential (V m ); they are, therefore, capable of recording action potentials (APs). Other mechanisms can give more sensitive voltage responses in specialized applications . Additionally, new fluorescent protein-based voltage sensors are being developed (23-26), with the promise of being able to genetically target specific cells in an organism. However, to date, hemicyanine dyes are the most universally used and applicable VSDs available. Indeed, among the most recent new advances enabled by these dyes, there has been recording of deep aberrant activity patterns in human hearts from transplant patients (27, 28) and recording V m spikes (∼1 ms) from individual dendritic spines (29-31).