Alex D. Reyes

Target-cell-specific facilitation and depression in neocortical circuits

In neocortical circuits, repetitively active neurons evoke unitary postsynaptic potentials (PSPs) whose peak amplitudes either increase (facilitate) or decrease (depress) progressively. To examine the basis for these different synaptic responses, we made simultaneous recordings from three classes of neurons in cortical layer 2/3. We induced repetitive action potentials in pyramidal cells and recorded the evoked unitary excitatory (E)PSPs in two classes of GABAergic neurons. We observed facilitation of EPSPs in bitufted GABAergic interneurons, many of which expressed somatostatin immunoreactivity. EPSPs recorded from multipolar interneurons, however, showed depression. Some of these neurons were immunopositive for parvalbumin. Unitary inhibitory (I)PSPs evoked by repetitive stimulation of a bitufted neuron also showed a less pronounced but significant difference between the two target neurons. Facilitation and depression involve presynaptic mechanisms, and because a single neuron can express both behaviors simultaneously, we infer that local differences in the molecular structure of presynaptic nerve terminals are induced by retrograde signals from different classes of target neurons. Because bitufted and multipolar neurons both formed reciprocal inhibitory connections with pyramidal cells, the results imply that the balance of activation between two recurrent inhibitory pathways in the neocortex depends on the frequency of action potentials in pyramidal cells.

The Asynchronous State in Cortical Circuits

Columns, Connections, and Correlations What is the nature of interactions between neurons in neural circuits? The prevalent hypothesis suggests that dense local connectivity causes nearby cortical neurons to receive substantial amounts of common input, which in turn leads to strong correlations between them. Now two studies challenge this view, which impacts our fundamental understanding of coding in the cortex. Ecker et al. (p. 584) investigated the statistics of correlated firing in pairs of neurons from area V1 of awake macaque monkeys. In contrast to previous studies, correlations turned out to be very low, irrespective of the stimulus being shown to the animals, the distances of the recording sites, and the similarity of the neurons receptive fields or response properties. In an accompanying modeling and recording paper, Renart et al. (p. 587) demonstrate how it is possible to have zero noise correlation, even among cells with common input. A general theoretical description of correlations in highly connected recurrent neuronal circuits. Correlated spiking is often observed in cortical circuits, but its functional role is controversial. It is believed that correlations are a consequence of shared inputs between nearby neurons and could severely constrain information decoding. Here we show theoretically that recurrent neural networks can generate an asynchronous state characterized by arbitrarily low mean spiking correlations despite substantial amounts of shared input. In this state, spontaneous fluctuations in the activity of excitatory and inhibitory populations accurately track each other, generating negative correlations in synaptic currents which cancel the effect of shared input. Near-zero mean correlations were seen experimentally in recordings from rodent neocortex in vivo. Our results suggest a reexamination of the sources underlying observed correlations and their functional consequences for information processing.

Correlation between neural spike trains increases with firing rate

Populations of neurons in the retina, olfactory system, visual and somatosensory thalamus, and several cortical regions show temporal correlation between the discharge times of their action potentials (spike trains). Correlated firing has been linked to stimulus encoding, attention, stimulus discrimination, and motor behaviour. Nevertheless, the mechanisms underlying correlated spiking are poorly understood, and its coding implications are still debated. It is not clear, for instance, whether correlations between the discharges of two neurons are determined solely by the correlation between their afferent currents, or whether they also depend on the mean and variance of the input. We addressed this question by computing the spike train correlation coefficient of unconnected pairs of in vitro cortical neurons receiving correlated inputs. Notably, even when the input correlation remained fixed, the spike train output correlation increased with the firing rate, but was largely independent of spike train variability. With a combination of analytical techniques and numerical simulations using ‘integrate-and-fire’ neuron models we show that this relationship between output correlation and firing rate is robust to input heterogeneities. Finally, this overlooked relationship is replicated by a standard threshold-linear model, demonstrating the universality of the result. This connection between the rate and correlation of spiking activity links two fundamental features of the neural code.

Synchrony-dependent propagation of firing rate in iteratively constructed networks in vitro.

The precise role of synchronous neuronal firing in signal encoding remains unclear. To examine what kinds of signals can be carried by synchrony, I reproduced a multilayer feedforward network of neurons in an in vitro slice preparation of rat cortex using an iterative procedure. When constant and time-varying frequency signals were delivered to the network, the firing of neurons in successive layers became progressively more synchronous. Notably, synchrony in the in vitro network developed even with uncorrelated input, persisted under a wide range of physiological conditions and was crucial for the stable propagation of rate signals. The firing rate was represented by a classical rate code in the initial layers, but switched to a synchrony-based code in the deeper layers.

Maturation of Intrinsic and Synaptic Properties of Layer 2/3 Pyramidal Neurons in Mouse Auditory Cortex

We investigated the development of L2/3 pyramidal cell (PC) circuitry in juvenile mice from postnatal day 10 (P10) to P29. Using whole cell recordings in an in vitro thalamocortical slice preparation, we examined the connection architecture and intrinsic and synaptic properties of PCs. The excitatory connections between PCs were highly localized: the probability of connection between PCs declined with intersomatic distance from 0.18 to about 0.05 over 150 microm, but did not vary with age. However, the mean and variance of the intrinsic and synaptic properties of PCs changed dramatically between P10 and P29. The input resistance, membrane time constant, and resting membrane potential decreased, leading to reduced neural excitability in older animals. Likewise, there were age-dependent decreases in the amplitude and decay time of the excitatory postsynaptic potentials as well as short-term synaptic depression. Both the intrinsic and synaptic properties underwent a transitional period between P10 and P18 prior to reaching steady state at P19-P29. We show that these properties combine to produce age-related differential synaptic responses to low- and high-frequency synaptic input that may contribute to differences in auditory processing during development.

Spatial Profile of Excitatory and Inhibitory Synaptic Connectivity in Mouse Primary Auditory Cortex

The role of local cortical activity in shaping neuronal responses is controversial. Among other questions, it is unknown how the diverse response patterns reported in vivo—lateral inhibition in some cases, approximately balanced excitation and inhibition (co-tuning) in others—compare to the local spread of synaptic connectivity. Excitatory and inhibitory activity might cancel each other out, or, whether one outweighs the other, receptive field properties might be substantially affected. As a step toward addressing this question, we used multiple intracellular recording in mouse primary auditory cortical slices to map synaptic connectivity among excitatory pyramidal cells and the two broad classes of inhibitory cells, fast-spiking (FS) and non-FS cells in the principal input layer. Connection probability was distance-dependent; the spread of connectivity, parameterized by Gaussian fits to the data, was comparable for all cell types, ranging from 85 to 114 μm. With brief stimulus trains, unitary synapses formed by FS interneurons were stronger than other classes of synapses; synapse strength did not correlate with distance between cells. The physiological data were qualitatively consistent with predictions derived from anatomical reconstruction. We also analyzed the truncation of neuronal processes due to slicing; overall connectivity was reduced but the spatial pattern was unaffected. The comparable spatial patterns of connectivity and relatively strong excitatory-inhibitory interconnectivity are consistent with a theoretical model where either lateral inhibition or co-tuning can predominate, depending on the structure of the input.

Synaptic mechanisms underlying auditory processing

In vivo voltage clamp recordings have provided new insights into the synaptic mechanisms that underlie processing in the primary auditory cortex. Of particular importance are the discoveries that excitatory and inhibitory inputs have similar frequency and intensity tuning, that excitation is followed by inhibition with a short delay, and that the duration of inhibition is briefer than expected. These findings challenge existing models of auditory processing in which broadly tuned lateral inhibition is used to limit excitatory receptive fields and suggest new mechanisms by which inhibition and short term plasticity shape neural responses.

A depolarizing inhibitory response to GABA in brainstem auditory neurons of the chick

Neurons in the brainstem auditory nuclei, n. magnocellularis and n. laminaris, of the chick are contacted by terminals containing the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). In this report we describe the physiological response of these neurons to GABA using an in vitro slice preparation. In brainstem auditory neurons, GABA produced a depolarization of up to 20 mV and an associated decrease in input resistance. This depolarization was inhibitory; action potentials generated by orthodromic synaptic drive, antidromic stimulation and intracellular current injection were prevented by GABA application. The GABA response still occurred when synaptic transmission was prevented by perfusing the slice with a medium containing low Ca2+ and high Mg2+ concentrations. Thus, the effects of GABA were directly on the postsynaptic neuron and not via an interneuron. Whole-cell voltage clamp of neurons revealed that the reversal potential of the inward current was approximately -45 mV, suggesting that the channel responsible for this response is not selective for Cl- or K+. Pharmacological analyses suggest that this GABA receptor has properties distinct from those typical of either GABAa or GABAb receptors. Although a similar response was observed with the GABAa agonist, muscimol, it was not blocked by the GABAa antagonist, bicuculline. The response was not evoked by the GABAb agonist, baclofen, and was not blocked by the GABAb antagonist phaclofen. This unusual depolarizing response is not a common feature of all brainstem neurons. Neurons located in the neighboring medial vestibular nucleus show a more traditional response to GABA application. At resting potential, these neurons show a hyperpolarizing or biphasic response associated with a decrease in input resistance and inhibition of their spontaneous activity. GABA-induced responses in the medial vestibular nucleus are blocked by bicuculline. These results suggest that an unusual form of the GABA receptor is present in the brainstem auditory system of the chick. It is possible that this form of GABA receptor provides an efficient mechanism for inhibiting the relatively powerful EPSPs received by brainstem auditory neurons, or it may play a trophic role in the afferent regulation of neuronal integrity in this system.

Layer and frequency dependencies of phase response properties of pyramidal neurons in rat motor cortex.

It is postulated that synchronous firing of cortical neurons plays an active role in cognitive functions of the brain. An important issue is whether pyramidal neurons in different cortical layers exhibit similar tendencies to synchronise. To address this issue, we performed intracellular and whole‐cell recordings of regular‐spiking pyramidal neurons in slice preparations of the rat motor cortex (18–45 days old) and analysed the phase response curves of these pyramidal neurons in layers 2/3 and 5. The phase response curve represents how an external stimulus affects the timing of spikes immediately after the stimulus in repetitively firing neurons. The phase response curve can be classified into two categories, type 1 (the spike is always advanced) and type 2 (the spike is advanced or delayed depending on the stimulus phase), and are important determinants of whether or not rhythmic synchronization of neuron pairs occurs. We found that pyramidal neurons in layer 2/3 tend to display type‐2 phase response curves whereas those in layer 5 tend to exhibit type‐1 phase response curves. The differences were prominent particularly in the gamma‐frequency range (20–45 Hz). Our results imply that the layer‐2/3 pyramidal neurons, when coupled mutually through fast excitatory synapses, may exhibit a much stronger tendency for rhythmic synchronization than layer‐5 neurons in the gamma‐frequency range.

Spatial Profile and Differential Recruitment of GABAB Modulate Oscillatory Activity in Auditory Cortex

The interplay between inhibition and excitation is at the core of cortical network activity. In many cortices, including auditory cortex (ACx), interactions between excitatory and inhibitory neurons generate synchronous network gamma oscillations (30–70 Hz). Here, we show that differences in the connection patterns and synaptic properties of excitatory–inhibitory microcircuits permit the spatial extent of network inputs to modulate the magnitude of gamma oscillations. Simultaneous multiple whole-cell recordings from connected fast-spiking interneurons and pyramidal cells in L2/3 of mouse ACx slices revealed that for intersomatic distances <50 μm, most inhibitory connections occurred in reciprocally connected (RC) pairs; at greater distances, inhibitory connections were equally likely in RC and nonreciprocally connected (nRC) pairs. Furthermore, the GABAB-mediated inhibition in RC pairs was weaker than in nRC pairs. Simulations with a network model that incorporated these features showed strong, gamma band oscillations only when the network inputs were confined to a small area. These findings suggest a novel mechanism by which oscillatory activity can be modulated by adjusting the spatial distribution of afferent input.