@article {49477, title = {Active dendritic integration and mixed neocortical network representations during an adaptive sensing behavior.}, journal = {Nature Neuroscience}, volume = {21}, year = {2018}, month = {2018 Oct 22}, pages = {1583-90}, abstract = {

Animals strategically scan the environment to form an accurate perception of their surroundings. Here we investigated the neuronal representations that mediate this behavior. Ca imaging and selective optogenetic manipulation during an active sensing task reveals that layer 5 pyramidal neurons in the vibrissae cortex produce a diverse and distributed representation that is required for mice to adapt their whisking motor strategy to changing sensory cues. The optogenetic perturbation degraded single-neuron selectivity and network population encoding through a selective inhibition of active dendritic integration. Together the data indicate that active dendritic integration in pyramidal neurons produces a nonlinearly mixed network representation of joint sensorimotor parameters that is used to transform sensory information into motor commands during adaptive behavior. The prevalence of the layer 5 cortical circuit motif suggests that this is a general circuit computation.

}, issn = {1546-1726}, doi = {10.1038/s41593-018-0254-6}, author = {Ranganathan, Gayathri N and Apostolides, Pierre F and Harnett, Mark T and Xu, Ning-long and Druckmann, Shaul and Magee, Jeffrey C} } @article {48413, title = {Deconstructing behavioral neuropharmacology with cellular specificity.}, journal = {Science (New York, N.Y.)}, volume = {356}, year = {2017}, month = {2017 Apr 07}, abstract = {

Behavior has molecular, cellular, and circuit determinants. However, because many proteins are broadly expressed, their acute manipulation within defined cells has been difficult. Here, we combined the speed and molecular specificity of pharmacology with the cell type specificity of genetic tools. DART (drugs acutely restricted by tethering) is a technique that rapidly localizes drugs to the surface of defined cells, without prior modification of the native target. We first developed an AMPAR antagonist DART, with validation in cultured neuronal assays, in slices of mouse dorsal striatum, and in behaving mice. In parkinsonian animals, motor deficits were causally attributed to AMPARs in indirect spiny projection neurons (iSPNs) and to excess phasic firing of tonically active interneurons (TANs). Together, iSPNs and TANs (i.e., D2 cells) drove akinesia, whereas movement execution deficits reflected the ratio of AMPARs in D2 versus D1 cells. Finally, we designed a muscarinic antagonist DART in one iteration, demonstrating applicability of the method to diverse targets.

}, issn = {1095-9203}, doi = {10.1126/science.aaj2161}, author = {Shields, Brenda C and Kahuno, Elizabeth and Kim, Charles and Apostolides, Pierre F and Brown, Jennifer and Lindo, Sarah and Mensh, Brett D and Dudman, Joshua T and Lavis, Luke D and Tadross, Michael R} } @article {47300, title = {Axonal filtering allows reliable output during dendritic plateau-driven complex spiking in CA1 neurons.}, journal = {Neuron}, volume = {89}, year = {2016}, month = {2016 Feb 17}, pages = {770-783}, abstract = {

In CA1 pyramidal neurons, correlated inputs trigger dendritic plateau potentials that drive neuronal plasticity and firing rate modulation. Given the strong electrotonic coupling between soma and axon, the \>25\ mV depolarization associated with the plateau could propagate through the axon to influence action potential initiation, propagation, and neurotransmitter release. We examined this issue in brain slices, awake mice, and a computational model. Despite profoundly inactivating somatic and proximal axon Na(+) channels, plateaus evoked action potentials that recovered to full amplitude in the distal axon (\>150\ μm) and triggered neurotransmitter release similar to regular spiking. This effect was due to strong attenuation of plateau depolarizations by axonal K(+) channels, allowing full axon repolarization and Na(+) channel deinactivation. High-pass filtering of dendritic plateaus by axonal K(+) channels should thus enable accurate transmission of gain-modulated firing rates, allowing neuronal firing to be efficiently read out by downstream regions as a simple rate code.

}, issn = {1097-4199}, doi = {10.1016/j.neuron.2015.12.040}, author = {Apostolides, Pierre F and Milstein, Aaron D and Grienberger, Christine and Bittner, Katie C and Magee, Jeffrey C} } @article {47087, title = {Inhibitory gating of input comparison in the CA1 microcircuit.}, journal = {Neuron}, volume = {87}, year = {2015}, month = {2015 Sep 23}, pages = {1274-89}, abstract = {

Spatial and temporal features of synaptic inputs engage integration mechanisms on multiple scales, including presynaptic release sites, postsynaptic dendrites, and networks of inhibitory interneurons. Here we investigate how these mechanisms cooperate to filter synaptic input in hippocampal area CA1. Dendritic recordings from CA1 pyramidal neurons reveal that proximal inputs from CA3 as well as distal inputs from entorhinal cortex layer III (ECIII) sum sublinearly or linearly at low firing rates due to feedforward inhibition, but sum supralinearly at high firing rates due to synaptic facilitation, producing a high-pass filter. However, during ECIII and CA3 input comparison, supralinear dendritic integration is dynamically balanced by feedforward and\ feedback inhibition, resulting in suppression of dendritic complex spiking. We find that a particular subpopulation of CA1 interneurons expressing neuropeptide Y (NPY) contributes prominently to this dynamic filter by integrating both ECIII and CA3 input pathways and potently inhibiting CA1 pyramidal neuron dendrites.

}, issn = {1097-4199}, doi = {10.1016/j.neuron.2015.08.025}, author = {Milstein, Aaron D and Bloss, Erik B and Apostolides, Pierre F and Vaidya, Sachin P and Dilly, Geoffrey A and Zemelman, Boris V and Magee, Jeffrey C} }