Membrane Potential-Dependent Modulation of Recurrent Inhibition in Rat Neocortex

Dynamic balance of excitation and inhibition is crucial for network stability and cortical processing, but it is unclear how this balance is achieved at different membrane potentials (Vm) of cortical neurons, as found during persistent activity or slow Vm oscillation. Here we report that a Vm-dependent modulation of recurrent inhibition between pyramidal cells (PCs) contributes to the excitation-inhibition balance. Whole-cell recording from paired layer-5 PCs in rat somatosensory cortical slices revealed that both the slow and the fast disynaptic IPSPs, presumably mediated by low-threshold spiking and fast spiking interneurons, respectively, were modulated by changes in presynaptic Vm. Somatic depolarization (>5 mV) of the presynaptic PC substantially increased the amplitude and shortened the onset latency of the slow disynaptic IPSPs in neighboring PCs, leading to a narrowed time window for EPSP integration. A similar increase in the amplitude of the fast disynaptic IPSPs in response to presynaptic depolarization was also observed. Further paired recording from PCs and interneurons revealed that PC depolarization increases EPSP amplitude and thus elevates interneuronal firing and inhibition of neighboring PCs, a reflection of the analog mode of excitatory synaptic transmission between PCs and interneurons. Together, these results revealed an immediate Vm-dependent modulation of cortical inhibition, a key strategy through which the cortex dynamically maintains the balance of excitation and inhibition at different states of cortical activity

Regulation of action potential waveforms by axonal GABAA receptors in cortical pyramidal neurons.

GABAA receptors distributed in somatodendritic compartments play critical roles in regulating neuronal activities, including spike timing and firing pattern; however, the properties and functions of GABAA receptors at the axon are still poorly understood. By recording from the cut end (bleb) of the main axon trunk of layer -5 pyramidal neurons in prefrontal cortical slices, we found that currents evoked by GABA iontophoresis could be blocked by picrotoxin, indicating the expression of GABAA receptors in axons. Stationary noise analysis revealed that single-channel properties of axonal GABAA receptors were similar to those of somatic receptors. Perforated patch recording with gramicidin revealed that the reversal potential of the GABA response was more negative than the resting membrane potential at the axon trunk, suggesting that GABA may hyperpolarize the axonal membrane potential. Further experiments demonstrated that the activation of axonal GABAA receptors regulated the amplitude and duration of action potentials (APs) and decreased the AP-induced Ca2+ transients at the axon. Together, our results indicate that the waveform of axonal APs and the downstream Ca2+ signals are modulated by axonal GABAA receptors

Activation of axonal GABA_A receptors shapes the AP waveform.

<p>A, Example traces showing the change in AP waveform after GABA iontophoresis to the axon bleb. <i>V</i>_m change was –3.9 mV in this bleb. The amplitude and the half-width of APs decreased to 95.6% and 86.8% of the control, respectively. B, Group data showing that activation of axonal GABA_A receptors shaped AP waveforms by regulating the amplitude and the half-width. Note that the recordings were performed under current-clamp and that the <i>V</i>_m could be manipulated by DC current injection. Black, GABA responses were hyperpolarizing; gray, depolarizing. The blebs were recorded with low-Cl⁻ ICS (7 mM [Cl⁻]_i). C, Increasing [Cl⁻]_i depolarized the <i>V</i>_m but still showed a shunting effect on AP waveforms. Amplitude and half-width were significantly reduced. Modified ICS (20 mM [Cl⁻]_i) was used for these recordings. ***, P<0.001, paired t-test. D, Bath application of PTX could block the GABA-induced <i>V</i>_m depolarization and its shunting effect on AP waveform. Modified ICS was used. E, Example traces showing that GABA application caused a shunting effect on APs evoked by electric shocks (asterisks), although GABA itself could evoke an AP (arrow). High-Cl⁻ ICS (75 mM [Cl⁻]_i) was used here.</p

Propagation of GABA-induced hyperpolarization at the axon regulates AP generation.

<p>A, DAB staining of recorded neurons. Simultaneous recording from the soma and axon bleb were performed in a pyramidal neuron (left), and GABA was applied to the axon trunk (right). The axon length was 239 µm in this case. The distance between the iontophoresis site and the soma was 117 µm. Scale bar: 100 µm (left); 50 µm (right). B, The sign of the effect of GABA (hyperpolarization or depolarization) depended on the <i>V</i>_m. Top, traces were taken from the bleb. Bottom, traces were the corresponding responses at the soma. The <i>V_m</i> was clamped through somatic DC current injection. Asterisk indicates application of GABA to the main trunk. C, Left, application of GABA to the axon increased the amplitude but decreased the half-width of propagating APs. GABA iontophoresis hyperpolarized the <i>V</i>_m by 2.3±0.4 mV (n = 7). Right, similar results were obtained when <i>V</i>_m was hyperpolarized by 2.8±0.3 mV (n = 5) through DC current injection. *, P<0.05; **, P<0.01, paired t-test. D, Example traces showing activation of axonal GABA_A receptors reduced firing probability and frequency. The distances between the iontophoresis site and the soma were 100 µm (distal axon) and 18 µm (AIS). E, Left, repetitive firing recorded at an axon bleb induced by 400 pA DC current injection at the soma before (black) and after (red) GABA application to the axon trunk. The arrow indicates GABA iontophoresis. Middle, instantaneous firing frequency of APs decreased after GABA application (same data as shown in the left). Right, group data showing a decrease in the mean frequency of APs after GABA iontophoresis at the axon trunk. **, P<0.01, paired t-test. Low-Cl⁻ ICS was used in these experiments.</p

The presence of GABA_A (but likely not GABA_B) receptors in the axon.

<p>A, Reversal potential of GABA responses (I_GABA) in the axon bleb. Left, representative currents induced by GABA application at different holding potentials (from –100 to –40 mV). At –60 mV (near reversal potential), GABA application induced no obvious change in baseline current (gray). Right, I-V curve of the GABA-induced responses shown on the left. B, I_GABA could be blocked by GABA_A receptor blocker PTX. Left, example traces before (black), during (gray) and after (Wash, dashed line) the bath application of PTX (25 µM). V_hold = –50 mV, GABA was applied via iontophoresis. Middle, time course of the effect of PTX. Right, group data showing the change of I_GABA during (n = 6) and after (n = 3) PTX application. The dashed line indicates 100% of control. C, Left, currents evoked by puffing baclofen (200 µM), a GABA_B receptor agonist, to the soma (16 psi, 15 ms). Right, no response was observed when baclofen was applied to the axon trunk (16 psi, 20 ms). D, Group data showing that GABA-induced currents at the axon blebs could not be blocked by the GABA_B receptor antagonist CGP 35348 (100 µM); however, PTX could diminish these responses. Different symbols indicate different cells.</p

Reversal potential of GABA responses (E_GABA) is more negative than the local RMP.

<p>A, Gramicidin perforated patch recording from an axon bleb. Arrow indicates the recorded bleb. Top, DIC image of the recording; middle, fluorescence image (unlabeled bleb); bottom, fluorescence image (labeled bleb, indicating rupture of patch membrane). Scale bar: 50 µm. B, Example traces showing GABA responses at different holding potentials (from –90 to –50 mV) before (black) and after the break-in (membrane rupture, gray). C, Comparison of E_GABA and RMP. Note that E_GABA at both the soma and the distal axon bleb were more hyperpolarized than their local RMP. *, P<0.05, paired t-test.</p

GABA receptors are located at axon bleb and trunk.

<p>A, Left, schematic diagram of bleb recording and GABA iontophoresis in a pyramidal neuron. Positive (but not negative) pulses could induce current responses. V_hold = –50 mV; iontophoresis pulses: 200 nA, 5 ms; retention current: –10 nA. Right, whole-cell recording from an axon bleb (top, fluorescence image; bottom, DIC image). Scale bar: 20 µm. The sharp electrode was used for GABA iontophoresis. Alexa Fluor 488 was added to the patch pipette solution so that the recording pipette was visible. B, Plot of the normalized GABA response as a function of the distance between the bleb and the tip of the iontophoresis electrode. Different symbols indicate different cells. The measurement of distance <i>L</i> is shown in the schematic diagram in panel A (indicated by arrows). C, GABA-induced responses could be observed when GABA was applied to the bleb (site <i>a</i>) or the main axon trunk (site <i>c</i>). The distance between sites <i>a</i> and <i>c</i> was approximately 50 µm, whereas that between <i>a</i> and <i>b</i> was approximately 25 µm. V_hold = –80 mV; iontophoresis pulses: 200 nA, 5 ms.</p

Transforming absolute value to categorical choice in primate superior colliculus during value-based decision making

Value-based decision making involves choosing from multiple options with different values. The authors identify a neural mechanism that directly transforms absolute values to categorical choices within the superior colliculus and which supports value-based decision making critical for real-world economic behaviours

High-dimensional topographic organization of visual features in the primate temporal lobe

Abstract The inferotemporal cortex supports our supreme object recognition ability. Numerous studies have been conducted to elucidate the functional organization of this brain area, but there are still important questions that remain unanswered, including how this organization differs between humans and non-human primates. Here, we use deep neural networks trained on object categorization to construct a 25-dimensional space of visual features, and systematically measure the spatial organization of feature preference in both male monkey brains and human brains using fMRI. These feature maps allow us to predict the selectivity of a previously unknown region in monkey brains, which is corroborated by additional fMRI and electrophysiology experiments. These maps also enable quantitative analyses of the topographic organization of the temporal lobe, demonstrating the existence of a pair of orthogonal gradients that differ in spatial scale and revealing significant differences in the functional organization of high-level visual areas between monkey and human brains