Conjunctive input processing drives feature selectivity in hippocampal CA1 neurons

Feature-selective firing allows networks to produce representations of the external and internal environments. Despite its importance, the mechanisms generating neuronal feature selectivity are incompletely understood. In many cortical microcircuits the integration of two functionally distinct inputs occurs nonlinearly through generation of active dendritic signals that drive burst firing and robust plasticity. To examine the role of this processing in feature selectivity, we recorded CA1 pyramidal neuron membrane potential and local field potential in mice running on a linear treadmill. We found that dendritic plateau potentials were produced by an interaction between properly timed input from entorhinal cortex and hippocampal CA3. These conjunctive signals positively modulated the firing of previously established place fields and rapidly induced new place field formation to produce feature selectivity in CA1 that is a function of both entorhinal cortex and CA3 input. Such selectivity could allow mixed network level representations that support context-dependent spatial maps.Howard Hughes Medical InstituteRikagaku Kenkyūjo (Japan

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

The Relationship between Single-Channel and Whole-Cell Conductance in the T-type Ca2+ Channel CaV3.1

In T-type Ca2+ channels, macroscopic IBa is usually smaller than ICa, but at high Ca2+ and Ba2+, single-channel conductance (γ) is equal. We investigated γ as a function of divalent concentration and compared it to macroscopic currents using CaV3.1 channels studied under similar experimental conditions (TEAo and Ki). Single-channel current-voltage relationships were nonlinear in a way similar to macroscopic open-channel I/Vs, so divalent γ was underestimated at depolarized voltages. To estimate divalent γ, concentration dependence, iDiv, was measured at voltages <−50 mV. Data were well described by Langmuir isotherms with γmax(Ca2+) of 9.5 ± 0.4 pS and γmax(Ba2+) of 10.3 ± 0.5 pS. Apparent KM was lower for Ca2+ (2.3 ± 0.7 mM) than for Ba2+ (7.9 ± 1.3 mM). A subconductance state with an amplitude 70% that of the main state was observed, the relative occupancy of which increased with increasing Ca2+. As predicted by γ, macroscopic GmaxCa was larger than GmaxBa at 5 mM (GmaxCa2+/Ba:2+1.43 ± 0.14) and similar at 60 mM (GmaxCa2+/Ba:2+1.10 ± 0.02). However, over the range of activation, ICa was larger than IBa under both conditions. This was a consequence of the fact that Vrev was more negative for IBa than for ICa, so that the driving force determining IBa was smaller than that determining ICa over the range of potentials in standard current-voltage relationships

Ion channel gradients in the apical tuft region of CA1 pyramidal neurons.

Dendritic ion channels play a critical role in shaping synaptic input and are fundamentally important for synaptic integration and plasticity. In the hippocampal region CA1, somato-dendritic gradients of AMPA receptors and the hyperpolarization-activated cation conductance (I(h)) counteract the effects of dendritic filtering on the amplitude, time-course, and temporal integration of distal Schaffer collateral (SC) synaptic inputs within stratum radiatum (SR). While ion channel gradients in CA1 distal apical trunk dendrites within SR have been well characterized, little is known about the patterns of ion channel expression in the distal apical tuft dendrites within stratum lacunosum moleculare (SLM) that receive distinct input from the entorhinal cortex via perforant path (PP) axons. Here, we measured local ion channels densities within these distal apical tuft dendrites to determine if the somato-dendritic gradients of I(h) and AMPA receptors extend into distal tuft dendrites. We also determined the densities of voltage-gated sodium channels and NMDA receptors. We found that the densities of AMPA receptors, I(h,) and voltage-gated sodium channels are similar in tuft dendrites in SLM when compared with distal apical dendrites in SR, while the ratio of NMDA receptors to AMPA receptors increases in tuft dendrites relative to distal apical dendrites within SR. These data indicate that the somato-dendritic gradients of I(h) and AMPA receptors in apical dendrites do not extend into the distal tuft, and the relative densities of voltage-gated sodium channels and NMDA receptors are poised to support nonlinear integration of correlated SC and PP input

Distance dependent scaling of HCN channels in SR does not extend into SLM.

<p>A. Representative current traces from dendrite-attached patches in proximal SR (100–200 µm from the soma, light grey), distal SR (250–350 µm from the soma, dark grey) or SLM (30–100 µm distal from the SR-SLM border, black) in response to a step depolarization to −135 mV from a holding potential of −45 mV. B. Average peak current measured 800–1000 ms after the voltage step from dendritic patches in pSR (cross circle, n = 20), dSR (open circle, n = 78) or SLM (closed circle, n = 31). *denotes significance (p<0.027, Mann Whitney) C. Representative whole cell current clamp voltage traces in response to a −150 pA current injection before and after application of ZD7288 from dendrites in distal SR (left) and SLM (right). Average resting potentials were ∼18 mV hyperpolarized in ZD7288, however traces are shown offset for comparison purposes. D. Apparent input resistance measured as described in methods for dendritic recordings in either dSR (open circles) or SLM (closed circles) before and after application of ZD7288 (dSR n = 7, SLM n = 8). Averages are shown in black and individual are in grey. E. Resting membrane potential for dendritic recordings from either dSR (open circles) or SLM (closed circles) before and after application of ZD7288. Paired individual measurements are shown in grey and averages in black. F. Percent sag recorded in dendrites within dSR (open circles) or SLM (closed circles). Data are shown as mean ± SEM.</p

Ion Channel Gradients in the Apical Tuft Region of CA1 Pyramidal Neurons - Na

<p>⁺<b>channel density is similar in SLM and distal SR.</b> A. Representative current traces from dendrite-attached patches in response to a voltage step from −85 mV to −25 mV in distal SR (left) and SLM (right). B. Representative ensemble average traces from the same dendrite as shown in A in response to voltage steps from −85 to −45, −25 and −5 mV. C. Average number of channels in dendrite-attached patches recorded in distal SR (open symbol) or SLM (closed symbol) calculated as described in methods. Data are shown as mean ± SEM in black and individual dendrites are shown in grey (dSR n = 26, SLM n = 19).</p

PP input to SLM recruits more NMDARs than SC input to SR.

<p>A. Evoked EPSPs in response to SC (left) or PP (right) stimulation in the absence (black) and presence (grey) of MK801 and APV. B. Percent of EPSP area blocked by MK801 and APV in response to SC (open symbol) or PP (closed symbol) stimulation (n = 10). ***denotes significance (p = 0.002, paired Wilcoxon). Average data are shown as mean ± SEM in black and individual patches are shown in grey.</p

mEPSC amplitude is similar in distal SR and SLM.

<p>A. Representative current traces in response to a local pressure application of hyperosmotic sucrose solution recorded from dendrites within distal SR (left) or SLM (right). B. Representative average mEPSC events in black recorded in distal SR (left) and SLM (right) aligned by the start of an event. Individual EPSC events are shown in grey. C. Left, Average amplitude of mEPSCs recorded in distal SR (open symbol, n = 4) or SLM (closed symbol, n = 7) from all dendrites (black) and individual dendrites (grey). Right, cumulative probability distribution of mEPSC amplitude recorded in dSR (grey, n = 4) or SLM (black, n = 7). D. Average rise time (circle) and decay time (square) of mEPSCs from distal SR (open symbols, n = 4) and SLM (closed symbols, n = 7). Data are shown as mean ± SEM.</p