Disinhibitory Circuitry Gates Associative Synaptic Plasticity in Olfactory Cortex.

Inhibitory microcircuits play an essential role in regulating cortical responses to sensory stimuli. Interneurons that inhibit dendritic or somatic integration act as gatekeepers for neural activity, synaptic plasticity, and the formation of sensory representations. Conversely, interneurons that selectively inhibit other interneurons can open gates through disinhibition. In the anterior piriform cortex, relief of inhibition permits associative LTP of excitatory synapses between pyramidal neurons. However, the interneurons and circuits mediating disinhibition have not been elucidated. In this study, we use an optogenetic approach in mice of both sexes to identify the inhibitory interneurons and disinhibitory circuits that regulate LTP. We focused on three prominent interneuron classes: somatostatin (SST), parvalbumin (PV), and vasoactive intestinal polypeptide (VIP) interneurons. We find that LTP is gated by the inactivation SST or PV interneurons and by the activation of VIP interneurons. Further, VIP interneurons strongly inhibit putative SST cells during LTP induction but only weakly inhibit PV interneurons. Together, these findings suggest that VIP interneurons mediate a disinhibitory circuit that gates synaptic plasticity during the formation of olfactory representations.SIGNIFICANCE STATEMENT Inhibitory interneurons stabilize neural activity during sensory processing. However, inhibition must also be modulated to allow sensory experience shape neural responses. In olfactory cortex, inhibition regulates activity-dependent increases in excitatory synaptic strength that accompany odor learning. We identify two inhibitory interneuron classes that act as gatekeepers preventing excitatory enhancement. We demonstrate that driving a third class of interneurons inhibits the gatekeepers and opens the gate for excitatory enhancement. All three inhibitory neuron classes comprise disinhibitory microcircuit motifs found throughout the cortex. Our findings suggest that a common disinhibitory microcircuit promotes changes in synaptic strength during sensory processing and learning.

Differential inhibition of pyramidal cells and inhibitory interneurons along the rostrocaudal axis of anterior piriform cortex.

The spatial representation of stimuli in sensory neocortices provides a scaffold for elucidating circuit mechanisms underlying sensory processing. However, the anterior piriform cortex (APC) lacks topology for odor identity as well as afferent and intracortical excitation. Consequently, olfactory processing is considered homogenous along the APC rostral-caudal (RC) axis. We recorded excitatory and inhibitory neurons in APC while optogenetically activating GABAergic interneurons along the RC axis. In contrast to excitation, we find opposing, spatially asymmetric inhibition onto pyramidal cells (PCs) and interneurons. PCs are strongly inhibited by caudal stimulation sites, whereas interneurons are strongly inhibited by rostral sites. At least two mechanisms underlie spatial asymmetries. Enhanced caudal inhibition of PCs is due to increased synaptic strength, whereas rostrally biased inhibition of interneurons is mediated by increased somatostatin-interneuron density. Altogether, we show differences in rostral and caudal inhibitory circuits in APC that may underlie spatial variation in odor processing along the RC axis.

Balanced feedforward inhibition and dominant recurrent inhibition in olfactory cortex.

Throughout the brain, the recruitment of feedforward and recurrent inhibition shapes neural responses. However, disentangling the relative contributions of these often-overlapping cortical circuits is challenging. The piriform cortex provides an ideal system to address this issue because the interneurons responsible for feedforward and recurrent inhibition are anatomically segregated in layer (L) 1 and L2/3 respectively. Here we use a combination of optical and electrical activation of interneurons to profile the inhibitory input received by three classes of principal excitatory neuron in the anterior piriform cortex. In all classes, we find that L1 interneurons provide weaker inhibition than L2/3 interneurons. Nonetheless, feedforward inhibitory strength covaries with the amount of afferent excitation received by each class of principal neuron. In contrast, intracortical stimulation of L2/3 evokes strong inhibition that dominates recurrent excitation in all classes. Finally, we find that the relative contributions of feedforward and recurrent pathways differ between principal neuron classes. Specifically, L2 neurons receive more reliable afferent drive and less overall inhibition than L3 neurons. Alternatively, L3 neurons receive substantially more intracortical inhibition. These three features--balanced afferent drive, dominant recurrent inhibition, and differential recruitment by afferent vs. intracortical circuits, dependent on cell class--suggest mechanisms for olfactory processing that may extend to other sensory cortices.

Interactions between behaviorally relevant rhythms and synaptic plasticity alter coding in the piriform cortex.

Understanding how neural and behavioral timescales interact to influence cortical activity and stimulus coding is an important issue in sensory neuroscience. In air-breathing animals, voluntary changes in respiratory frequency alter the temporal patterning olfactory input. In the olfactory bulb, these behavioral timescales are reflected in the temporal properties of mitral/tufted (M/T) cell spike trains. As the odor information contained in these spike trains is relayed from the bulb to the cortex, interactions between presynaptic spike timing and short-term synaptic plasticity dictate how stimulus features are represented in cortical spike trains. Here, we demonstrate how the timescales associated with respiratory frequency, spike timing, and short-term synaptic plasticity interact to shape cortical responses. Specifically, we quantified the timescales of short-term synaptic facilitation and depression at excitatory synapses between bulbar M/T cells and cortical neurons in slices of mouse olfactory cortex. We then used these results to generate simulated M/T population synaptic currents that were injected into real cortical neurons. M/T population inputs were modulated at frequencies consistent with passive respiration or active sniffing. We show how the differential recruitment of short-term plasticity at breathing versus sniffing frequencies alters cortical spike responses. For inputs at sniffing frequencies, cortical neurons linearly encoded increases in presynaptic firing rates with increased phase-locked, firing rates. In contrast, at passive breathing frequencies, cortical responses saturated with changes in presynaptic rate. Our results suggest that changes in respiratory behavior can gate the transfer of stimulus information between the olfactory bulb and cortex.

Balanced synaptic input shapes the correlation between neural spike trains.

Stimulus properties, attention, and behavioral context influence correlations between the spike times produced by a pair of neurons. However, the biophysical mechanisms that modulate these correlations are poorly understood. With a combined theoretical and experimental approach, we show that the rate of balanced excitatory and inhibitory synaptic input modulates the magnitude and timescale of pairwise spike train correlation. High rate synaptic inputs promote spike time synchrony rather than long timescale spike rate correlations, while low rate synaptic inputs produce opposite results. This correlation shaping is due to a combination of enhanced high frequency input transfer and reduced firing rate gain in the high input rate state compared to the low state. Our study extends neural modulation from single neuron responses to population activity, a necessary step in understanding how the dynamics and processing of neural activity change across distinct brain states.

Development of inhibitory timescales in auditory cortex.

The time course of inhibition plays an important role in cortical sensitivity, tuning, and temporal response properties. We investigated the development of L2/3 inhibitory circuitry between fast-spiking (FS) interneurons and pyramidal cells (PCs) in auditory thalamocortical slices from mice between postnatal day 10 (P10) and P29. We found that the maturation of the intrinsic and synaptic properties of both FS cells and their connected PCs influence the timescales of inhibition. FS cell firing rates increased with age owing to decreased membrane time constants, shorter afterhyperpolarizations, and narrower action potentials. Between FS-PC pairs, excitatory postsynaptic potentials (EPSPs) and inhibitory postsynaptic potentials (IPSPs) changed with age. The latencies, rise, and peak times of the IPSPs, as well as the decay constants of both EPSPs and IPSPs decreased between P10 and P29. In addition, decreases in short-term depression at excitatory PC-FS synapses resulted in more sustained synaptic responses during repetitive stimulation. Finally, we show that during early development, the temporal properties that influence the recruitment of inhibition lag those of excitation. Taken together, our results suggest that the changes in the timescales of inhibitory recruitment coincide with the development of the tuning and temporal response properties of auditory cortical networks.

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 microm, 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 GABA(B)-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.

Divergent Neural Pathways Emanating from the Lateral Parabrachial Nucleus Mediate Distinct Components of the Pain Response.

The lateral parabrachial nucleus (lPBN) is a major target of spinal projection neurons conveying nociceptive input into supraspinal structures. However, the functional role of distinct lPBN efferents in diverse nocifensive responses have remained largely uncharacterized. Here we show that that the lPBN is required for escape behaviors and aversive learning to noxious stimulation. In addition, we find that two populations of efferent neurons from different regions of the lPBN collateralize to distinct targets. Activation of efferent projections to the ventromedial hypothalamus (VMH) or lateral periaqueductal gray (lPAG) drives escape behaviors, whereas activation of lPBN efferents to the bed nucleus stria terminalis (BNST) or central amygdala (CEA) generates an aversive memory. Finally, we provide evidence that dynorphin-expressing neurons, which span cytoarchitecturally distinct domains of the lPBN, are required for aversive learning.

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.

Inhibition by Somatostatin Interneurons in Olfactory Cortex.

Inhibitory circuitry plays an integral role in cortical network activity. The development of transgenic mouse lines targeting unique interneuron classes has significantly advanced our understanding of the functional roles of specific inhibitory circuits in neocortical sensory processing. In contrast, considerably less is known about the circuitry and function of interneuron classes in piriform cortex, a paleocortex responsible for olfactory processing. In this study, we sought to utilize transgenic technology to investigate inhibition mediated by somatostatin (SST) interneurons onto pyramidal cells (PCs), parvalbumin (PV) interneurons, and other interneuron classes. As a first step, we characterized the anatomical distributions and intrinsic properties of SST and PV interneurons in four transgenic lines (SST-cre, GIN, PV-cre, and G42) that are commonly interbred to investigate inhibitory connectivity. Surprisingly, the distributions SST and PV cell subtypes targeted in the GIN and G42 lines were sparse in piriform cortex compared to neocortex. Moreover, two-thirds of interneurons recorded in the SST-cre line had electrophysiological properties similar to fast spiking (FS) interneurons rather than regular (RS) or low threshold spiking (LTS) phenotypes. Nonetheless, like neocortex, we find that SST-cells broadly inhibit a number of unidentified interneuron classes including putatively identified PV cells and surprisingly, other SST cells. We also confirm that SST-cells inhibit pyramidal cell dendrites and thus, influence dendritic integration of afferent and recurrent inputs to the piriform cortex. Altogether, our findings suggest that SST interneurons play an important role in regulating both excitation and the global inhibitory network during olfactory processing.

Parallel processing of sensory input by bursts and isolated spikes.

Burst firing is commonly observed in many sensory systems and is proposed to transmit information reliably. Although a number of biophysical burst mechanisms have been identified, the relationship between burst dynamics and information transfer is uncertain. Electrosensory pyramidal cells have a well defined backpropagation-dependent burst mechanism. We used in vivo, in vitro, and modeling approaches to investigate pyramidal cell responses to mimics of behaviorally relevant sensory input. We found that within a given spike train, bursts are biased toward low-frequency events while isolated spikes simultaneously code for the entire frequency range. We also demonstrated that burst dynamics are essential for optimal feature detection but are not required for stimulus estimation. We conclude that burst and spike dynamics can segregate a single spike train into two parallel and complementary streams of information transfer.

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.

Interval coding. I. Burst interspike intervals as indicators of stimulus intensity.

Short interspike intervals such as those that occur during burst firing are hypothesized to be distinct features of the neural code. Although a number of correlations between the occurrence of burst events and aspects of the stimulus have been identified, the relationship between burst characteristics and information transfer is uncertain. Pyramidal cells in the electrosensory lobe of the weakly electric fish, Apteronotus leptorhynchus, respond to dynamic broadband electrosensory stimuli with bursts and isolated spikes. In the present study, we mimic synaptic input during sensory stimulation by direct stimulation of electrosensory pyramidal cells with broadband current in vitro. The pyramidal cells respond to this stimulus with burst interspike intervals (ISIs) that are reliably and precisely correlated with the intensity of stimulus upstrokes. We found burst ISIs must differ by a minimum of 2 ms to discriminate, with low error, differences in stimulus intensity. Based on these results, we define and quantify a candidate interval code for the processing of sensory input. Finally, we demonstrate that interval coding is restricted to short ISIs such as those generated in burst events and that the proposed interval code is distinct from rate and timing codes.

Interval coding. II. Dendrite-dependent mechanisms.

The rich temporal structure of neural spike trains provides multiple dimensions to code dynamic stimuli. Popular examples are spike trains from sensory cells where bursts and isolated spikes can serve distinct coding roles. In contrast to analyses of neural coding, the cellular mechanics of burst mechanisms are typically elucidated from the neural response to static input. Bridging the mechanics of bursting with coding of dynamic stimuli is an important step in establishing theories of neural coding. Electrosensory lateral line lobe (ELL) pyramidal neurons respond to static inputs with a complex dendrite-dependent burst mechanism. Here we show that in response to dynamic broadband stimuli, these bursts lack some of the electrophysiological characteristics observed in response to static inputs. A simple leaky integrate-and-fire (LIF)-style model with a dendrite-dependent depolarizing afterpotential (DAP) is sufficient to match both the output statistics and coding performance of experimental spike trains. We use this model to investigate a simplification of interval coding where the burst interspike interval (ISI) codes for the scale of a canonical upstroke rather than a multidimensional stimulus feature. Using this stimulus reduction, we compute a quantization of the burst ISIs and the upstroke scale to show that the mutual information rate of the interval code is maximized at a moderate DAP amplitude. The combination of a reduced description of ELL pyramidal cell bursting and a simplification of the interval code increases the generality of ELL burst codes to other sensory modalities.

Dynamically interacting processes underlie synaptic plasticity in a feedback pathway.

Descending feedback is a common feature of sensory systems. Characterizing synaptic plasticity in feedback inputs is essential for delineating the role of feedback in sensory processing. In this study, we demonstrate that multiple interacting processes underlie the dynamics of synaptic potentiation in one such sensory feedback pathway. We use field recording and modeling to investigate the interaction between the transient high-magnitude potentiation (200-300%) elicited during tetanic stimulation of the feedback pathway and the lower magnitude posttetanic potentiation (PTP; ~30%) that slowly decays on cessation of the tetanus. The amplitude of the observed transient potentiation is graded with stimulus frequency. In contrast, the induction of PTP has a stimulus frequency threshold between 1 and 5 Hz, and its amplitude is independent of stimulus frequency. We suggest that the threshold for PTP induction may be linked to a minimum level of sustained potentiation (MSP) during repetitive trains of stimuli. We have developed a novel model that describes the interaction between the transient plasticity observed during train stimulation and the generation of PTP. The model combines a multiplicative, facilitation-depression-type (FD) model that describes the transient plasticity, with an enzymatic network that describes the dynamics of PTP. The model links transient plasticity to PTP through an input term that reflects MSP. The stratum fibrosum-pyramidal cell (StF-PC) synapse investigated in this study is the terminus of a feedback pathway to the electrosensory lateral line lobe (ELL) of a weakly electric gymnotiform fish. Dynamic plasticity at the StF-PC synapse may contribute to the putative role of this feedback pathway as a sensory searchlight.