Feedforward Inhibitory Circuit Research Articles

A primary sensory cortical interareal feedforward inhibitory circuit for tacto-visual integration

Tactile sensation and vision are often both utilized for the exploration of objects that are within reach though it is not known whether or how these two distinct sensory systems combine such information. Here in mice, we used a combination of stereo photogrammetry for 3D reconstruction of the whisker array, brain-wide anatomical tracing and functional connectivity analysis to explore the possibility of tacto-visual convergence in sensory space and within the circuitry of the primary visual cortex (VISp). Strikingly, we find that stimulation of the contralateral whisker array suppresses visually evoked activity in a tacto-visual sub-region of VISp whose visual space representation closely overlaps with the whisker search space. This suppression is mediated by local fast-spiking interneurons that receive a direct cortico-cortical input predominantly from layer 6 neurons located in the posterior primary somatosensory barrel cortex (SSp-bfd). These data demonstrate functional convergence within and between two primary sensory cortical areas for multisensory object detection and recognition.

The Anterolateral Barrel Subfield Differs from the Posteromedial Barrel Subfield in the Morphology and Cell Density of Parvalbumin-Positive GABAergic Interneurons.

Layer 4 of the rodent somatosensory cortex has unitary structures called barrels that receive tactile information from individual vibrissae. Barrels in the anterolateral barrel subfield (ALBSF) are much smaller and have gained less attention than larger barrels in the posteromedial barrel subfield (PMBSF), though the former outnumber the latter. We compared the morphological features of barrels between the ALBSF and PMBSF in male mice using deformation-free tangential sections and confocal optical slice-based, precise reconstructions of barrels. The average volume of a single barrel in the ALBSF was 34.7% of that in the PMBSF, but the numerical density of parvalbumin (PV)-positive interneurons in the former was 1.49 times higher than that in the latter. Moreover, PV neuron density in septa was 2.08 times higher in the ALBSF than that in the PMBSF. The proportions of PV neuron number to both all neuron number and all GABAergic neuron number in the ALBSF were also higher than those in the PMBSF. Somata of PV neurons in barrels and septa in the ALBSF received 1.64 and 1.50 times more vesicular glutamate transporter Type 2-labeled boutons than those in the PMBSF, suggesting more potent feedforward inhibitory circuits in the ALBSF. The mode of connectivity through dendritic gap junctions among PV neurons also differed between the ALBSF and PMBSF. Clusters of smaller unitary structures containing a higher density of representative GABAergic interneurons with differential morphological features in the ALBSF suggest a division of functional roles in the two vibrissa-barrel systems, as has been demonstrated by behavioral studies.

A feedforward inhibitory premotor circuit for auditory–vocal interactions in zebra finches

During vocal exchanges, hearing specific auditory signals can provoke vocal responses or suppress vocalizations to avoid interference. These abilities result in the widespread phenomenon of vocal turn taking, yet little is known about the neural circuitry that regulates the input-dependent timing of vocal replies. Previous work in vocally interacting zebra finches has highlighted the importance of premotor inhibition for precisely timed vocal output. By developing physiologically constrained mathematical models, we derived circuit mechanisms based on feedforward inhibition that enable both the temporal modulation of vocal premotor drive as well as auditory suppression of vocalization during listening. Extracellular recordings in HVC during the listening phase confirmed the presence of auditory-evoked response patterns in putative inhibitory interneurons, along with corresponding signatures of auditory-evoked activity suppression. Further, intracellular recordings of identified neurons projecting to HVC from the upstream sensorimotor nucleus, nucleus interfacialis (NIf), shed light on the timing of auditory inputs to this network. The analysis of incrementally time-lagged interactions between auditory and premotor activity in the model resulted in the prediction of a window of auditory suppression, which could be, in turn, verified in behavioral data. A phasic feedforward inhibition model consistently explained the experimental results. This mechanism highlights a parsimonious and generalizable principle for how different driving inputs (vocal and auditory related) can be integrated in a single sensorimotor circuit to regulate two opposing vocal behavioral outcomes: the controlled timing of vocal output or the suppression of overlapping vocalizations.

Fast and slow feedforward inhibitory circuits for cortical odor processing.

Feedforward inhibitory circuits are key contributors to the complex interplay between excitation and inhibition in the brain. Little is known about the function of feedforward inhibition in the primary olfactory (piriform) cortex. Using in vivo two-photon-targeted patch clamping and calcium imaging in mice, we find that odors evoke strong excitation in two classes of interneurons - neurogliaform (NG) cells and horizontal (HZ) cells - that provide feedforward inhibition in layer 1 of the piriform cortex. NG cells fire much earlier than HZ cells following odor onset, a difference that can be attributed to the faster odor-driven excitatory synaptic drive that NG cells receive from the olfactory bulb. As a result, NG cells strongly but transiently inhibit odor-evoked excitation in layer 2 principal cells, whereas HZ cells provide more diffuse and prolonged feedforward inhibition. Our findings reveal unexpected complexity in the operation of inhibition in the piriform cortex.

A Novel Layer 4 Corticofugal Cell Type/Projection Involved in Thalamo-Cortico-Striatal Sensory Processing

In sensory cortices, the information flow has been thought to be processed vertically across cortical layers, with layer 4 being the major thalamo-recipient which relays thalamic signals to layer 2/3, which in turn transmits thalamic information to layer 5 and 6 to then leave the cortex to reach subcortical and cortical long-range structures. Although several exceptions to this model have been described, neurons in layer 4 are still considered to establish only local (i.e., interlaminar and short-range) connections. Here, taking advantage of anatomic, electrophysiological, and optogenetic techniques, we describe, for the first time, a long-range corticostriatal class of pyramidal neurons in layer 4 (CS-L4) of the mouse auditory cortex that receive direct thalamic inputs. The CS-L4 neurons are embedded in a feedforward inhibitory circuit involving local parvalbumin neurons and establish connections in the posterior striatum in yet another feedforward inhibitory thalamo→cortico(L4)→striatal circuit which potentially contributes in controlling control the output of striatal spiny projection neurons.SIGNIFICANCE STATEMENTThe assumption has been that layer 4 neurons are the main thalamic recipient layer, projecting to the upper cortical layer 2/3. However, no study has revealed a detailed understanding of the circuit mechanisms by which layer 4 sends a projection to a subcortical structure, such as the striatum, and differentially innervate the spiny projection neurons (SPNs) and intrastriatal parvalbumin-expressing neurons. For the first time, our results demonstrate that the auditory cortex projects to the posterior part of the dorsal striatum via pyramidal neurons located in layer 4 (CS-L4 neurons). Here we propose a new wiring diagram that implemented the old one, in which layer 4 is not only involved in the transfer of thalamic input to the upper layer 2/3, but can also exert a direct top-down control, bypassing intracortical processing of subcortical structures, such as the posterior part of the dorsal striatum. This poses a new conceptual cell element (CS-L4 neurons) for experimental and theoretical work of the cortical function.

Acetylcholine prioritises direct synaptic inputs from entorhinal cortex to CA1 by differential modulation of feedforward inhibitory circuits

Acetylcholine release in the hippocampus plays a central role in the formation of new memory representations. An influential but largely untested theory proposes that memory formation requires acetylcholine to enhance responses in CA1 to new sensory information from entorhinal cortex whilst depressing inputs from previously encoded representations in CA3. Here, we show that excitatory inputs from entorhinal cortex and CA3 are depressed equally by synaptic release of acetylcholine in CA1. However, feedforward inhibition from entorhinal cortex exhibits greater depression than CA3 resulting in a selective enhancement of excitatory-inhibitory balance and CA1 activation by entorhinal inputs. Entorhinal and CA3 pathways engage different feedforward interneuron subpopulations and cholinergic modulation of presynaptic function is mediated differentially by muscarinic M3 and M4 receptors, respectively. Thus, our data support a role and mechanisms for acetylcholine to prioritise novel information inputs to CA1 during memory formation.

The paraventricular thalamus provides a polysynaptic brake on limbic CRF neurons to sex-dependently blunt binge alcohol drinking and avoidance behavior in mice

Bed nucleus of the stria terminalis (BNST) neurons that synthesize corticotropin-releasing factor (CRF) drive binge alcohol drinking and anxiety. Here, we found that female C57BL/6J mice binge drink more than males and have greater basal BNSTCRF neuron excitability and synaptic excitation. We identified a dense VGLUT2 + synaptic input from the paraventricular thalamus (PVT) that releases glutamate directly onto BNSTCRF neurons but also engages a large BNST interneuron population to ultimately inhibit BNSTCRF neurons, and this polysynaptic PVTVGLUT2-BNSTCRF circuit is more robust in females than males. Chemogenetic inhibition of the PVTBNST projection promoted binge alcohol drinking only in female mice, while activation reduced avoidance behavior in both sexes. Lastly, repeated binge drinking produced a female-like phenotype in the male PVT-BNSTCRF excitatory synapse without altering the function of PVTBNST neurons per se. Our data describe a complex, feedforward inhibitory PVTVGLUT2-BNSTCRF circuit that is sex-dependent in its function, behavioral roles, and alcohol-induced plasticity.

Kappa opioid receptor modulation of excitatory drive onto nucleus accumbens fast-spiking interneurons.

The dynorphin/kappa opioid receptor (KOR) system within the nucleus accumbens (NAc) contributes to affective states. Parvalbumin fast-spiking interneurons (PV-FSIs), a key component of feedforward inhibition, participate in integration of excitatory inputs to the NAc by robustly inhibiting select populations of medium spiny output neurons, therefore greatly influencing NAc dependent behavior. How the dynorphin/KOR system regulates feedforward inhibition in the NAc remains unknown. Here, we elucidate the molecular mechanisms of KOR inhibition ofexcitatory transmission onto NAc PV-FSIs using a combination of whole-cell patch-clamp electrophysiology, optogenetics, pharmacology, and a parvalbumin reporter mouse. We find that postsynaptic KOR stimulation induces long-term depression (LTD) of excitatory synapses ontoPV-FSI by stimulating the endocytosis of AMPARs via a PKA and calcineurin-dependent mechanism. Furthermore, KOR regulation of PV-FSI synapses are input specific, inhibiting thalamic but not cortical inputs. Finally, following acute stress, a protocol known to elevate dynorphin/KOR signaling in the NAc, KOR agonists no longer inhibit excitatory transmission ontoPV-FSI. In conclusion, we delineate pathway-specific mechanisms mediating KOR control of feedforward inhibitory circuits in the NAc and provide evidence for the recruitment of this system in response to stress.

Molecular and Electrophysiological Characterization of Dorsal Horn Neurons in a GlyT2-iCre-tdTomato Mouse Line.

PurposeSpinal glycinergic neurons function as critical elements of a spinal gate for pain and itch. We have recently documented that spinal PKCγ+ neurons receive the feedforward inhibitory input driven by Aβ primary afferent. The glycinergic neurons control the excitability of PKCγ+ neurons and therefore gate mechanical allodynia. However, a dynamic or electrophysiological analysis of the synaptic drive on spinal glycinergic interneurons from primary afferent fibers is largely absent. The present study was aimed to analyze the synaptic dynamics between spinal glycinergic interneurons and primary afferents using a genetic labeled animal model.Materials and MethodsThe GlyT2-P2A-iCre mice were constructed by the CRISPR/Cas9 technology. The GlyT2-iCre-tdTomato mice were then generated by crossing the GlyT2-P2A-iCre mice with fluorescent reporter mice. Patch-clamp whole-cell recordings were used to analyze the dynamic synaptic inputs to glycinergic neurons in GlyT2-iCre-tdTomato mice. The distribution of GlyT2-tdTomato neurons in the spinal dorsal horn was examined by the immunohistochemistry method. The firing pattern and morphological features of GlyT2-tdTomato neurons were also examined by electrophysiological recordings and intracellular injection of biocitin.ResultsThe GlyT2-P2A-iCre and GlyT2-tdTomato mice were successfully constructed. GlyT2-tdTomato fluorescence was colocalized extensively with immunoreactivity of glycine, GlyT2 and Pax2 in somata, confirming the selective expression of the transgene in glycinergic neurons. GlyT2-tdTomato neurons were mainly distributed in spinal lamina IIi through IV. The firing pattern and morphological properties of GlyT2-tdTomato neurons met the features of tonic central or islet type of spinal inhibitory interneurons. The majority (72.1%) of the recorded GlyT2-tdTomato neurons received primary inputs from Aβ fibers.ConclusionThe present study indicated that spinal GlyT2-positive glycinergic neurons mainly received primary afferent Aβ fiber inputs; the GlyT2-P2A-iCre and GlyT2-tdTomato mice provided a useful animal model to further investigate the function of the GlyT2+-PKCγ+ feedforward inhibitory circuit in both physiological and pathological conditions.

Spinal GABAergic neurons are under feed-forward inhibitory control driven by Aδ and C fibers in Gad2 td-Tomato mice.

BackgroundSpinal GABAergic neurons act as a critical modulator in sensory transmission like pain or itch. The monosynaptic or polysynaptic primary afferent inputs onto GABAergic neurons, along with other interneurons or projection neurons make up the direct and feed-forward inhibitory neural circuits. Previous research indicates that spinal GABAergic neurons mainly receive excitatory inputs from Aδ and C fibers. However, whether they are controlled by other inhibitory sending signals is not well understood.MethodsWe applied a transgenic mouse line in which neurons co-expressed the GABA-synthesizing enzyme Gad65 and the enhanced red fluorescence (td-Tomato) to characterize the features of morphology and electrophysiology of GABAergic neurons. Patch-clamp whole cell recordings were used to record the evoked postsynaptic potentials of fluorescent neurons in spinal slices in response to dorsal root stimulation.ResultsWe demonstrated that GABAergic neurons not only received excitatory drive from peripheral Aβ, Aδ and C fibers, but also received inhibitory inputs driven by Aδ and C fibers. The evoked inhibitory postsynaptic potentials (eIPSPs) mediated by C fibers were mainly Glycinergic (66.7%) as well as GABAergic mixed with Glycinergic (33.3%), whereas the inhibition mediated by Aδ fibers was predominately both GABA and Glycine-dominant (57.1%), and the rest of which was purely Glycine-dominant (42.9%).ConclusionThese results indicated that spinal GABAergic inhibitory neurons are under feedforward inhibitory control driven by primary C and Aδ fibers, suggesting that this feed-forward inhibitory pathway may play an important role in balancing the excitability of GABAergic neurons in spinal dorsal horn.

Extracellular GABA waves regulate coincidence detection in excitatory circuits.

Key points Rapid changes in neuronal network activity trigger widespread waves of extracellular GABA in hippocampal neuropil.Elevations of extracellular GABA narrow the coincidence detection window for excitatory inputs to CA1 pyramidal cells.GABA transporters control the effect of extracellular GABA on coincidence detection.Small changes in the kinetics of dendritic excitatory currents amplify when reaching the soma. Coincidence detection of excitatory inputs by principal neurons underpins the rules of signal integration and Hebbian plasticity in the brain. In the hippocampal circuitry, detection fidelity is thought to depend on the GABAergic synaptic input through a feedforward inhibitory circuit also involving the hyperpolarisation‐activated Ih current. However, afferent connections often bypass feedforward circuitry, suggesting that a different GABAergic mechanism might control coincidence detection in such cases. To test whether fluctuations in the extracellular GABA concentration [GABA] could play a regulatory role here, we use a GABA 'sniffer' patch in acute hippocampal slices of the rat and document strong dependence of [GABA] on network activity. We find that blocking GABAergic signalling strongly widens the coincidence detection window of direct excitatory inputs to pyramidal cells whereas increasing [GABA] through GABA uptake blockade shortens it. The underlying mechanism involves membrane‐shunting tonic GABAA receptor current; it does not have to rely on Ih but depends strongly on the neuronal GABA transporter GAT‐1. We use dendrite‐soma dual patch‐clamp recordings to show that the strong effect of membrane shunting on coincidence detection relies on nonlinear amplification of changes in the decay of dendritic synaptic currents when they reach the soma. Our results suggest that, by dynamically regulating extracellular GABA, brain network activity can optimise signal integration rules in local excitatory circuits.

Synaptic Dynamics of the Feed-forward Inhibitory Circuitry Gating Mechanical Allodynia in Mice.

The authors' previous studies have found that spinal protein kinase C γ expressing neurons are involved in the feed-forward inhibitory circuit gating mechanical allodynia in the superficial dorsal horn. The authors hypothesize that nerve injury enhances the excitability of spinal protein kinase C γ expressing interneurons due to disinhibition of the feed-forward inhibitory circuit, and enables Aβ primary inputs to activate spinal protein kinase C γ expressing interneurons. Prkcg-P2A-tdTomato mice were constructed using the clustered regularly interspaced short palindromic repeats and clustered regularly interspaced short palindromic repeats-associated nuclease 9 technology, and were used to analyze the electrophysiologic properties of spinal protein kinase C γ expressing neurons in both normal conditions and pathologic conditions induced by chronic constriction injury of the sciatic nerve. Patch-clamp whole cell recordings were used to identify the nature of the dynamic synaptic drive to protein kinase C γ expressing neurons. Aβ fiber stimulation evoked a biphasic synaptic response in 42% (31 of 73) of protein kinase C γ expressing neurons. The inhibitory components of the biphasic synaptic response were blocked by both strychnine and bicuculline in 57% (16 of 28) of neurons. Toll-like receptor 5 immunoreactive fibers made close contact with protein kinase C γ expressing neurons. After nerve injury, the percentage of neurons double-labeled for c-fos and Prkcg-P2A-tdTomato in animals walking on a rotarod was significantly higher than that in the nerve injury animals (4.1% vs. 9.9%, 22 of 539 vs. 54 of 548,P < 0.001). Aβ fiber stimulation evoked burst action potentials in 25.8% (8 of 31) of protein kinase C γ expressing neurons in control animals, while the proportion increased to 51.1% (23 of 45) in nerve injury animals (P = 0.027). The Prkcg-P2A-tdTomato mice the authors constructed provide a useful tool for further analysis on how the spinal allodynia gate works. The current study indicated that nerve injury enhanced the excitability of spinal protein kinase C γ expressing interneurons due to disinhibition of the feed-forward inhibitory circuit, and enabled Aβ primary inputs to activate spinal protein kinase C γ expressing interneurons.

Neural circuits underlying a psychotherapeutic regimen for fear disorders.

A psychotherapeutic regimen that uses alternating bilateral sensory stimulation (ABS) has been used to treat post-traumatic stress disorder. However, the neural basis that underlies the long-lasting effect of this treatment-described as eye movement desensitization and reprocessing-has not been identified. Here we describe a neuronal pathway driven by the superior colliculus (SC) that mediates persistent attenuation of fear. We successfully induced a lasting reduction in fear in mice by pairing visual ABS with conditioned stimuli during fear extinction. Among the types of visual stimulation tested, ABS provided the strongest fear-reducing effect and yielded sustained increases in the activities of the SC and mediodorsal thalamus (MD). Optogenetic manipulation revealed that the SC-MD circuit was necessary and sufficient to prevent the return of fear. ABS suppressed the activity of fear-encoding cells and stabilized inhibitory neurotransmission in the basolateral amygdala through a feedforward inhibitory circuit from the MD. Together, these results reveal the neural circuit that underlies an effective strategy for sustainably attenuating traumatic memories.

Complex and spatially segregated auditory inputs of the mouse superior colliculus.

Key points Although the visual circuits in the superior colliculus (SC) have been thoroughly examined, the auditory circuits lack equivalent scrutiny.SC neurons receiving auditory inputs in mice were characterized and three distinguishable types of neurons were found.The auditory pathways from external nuclei of the inferior colliculus (IC) were characterized, and a novel direct inhibitory connection and an excitation that drives feed‐forward inhibitory circuits within the SC were found.The direct excitatory and inhibitory inputs exhibited distinct arbourization patterns in the SC.These findings suggest functional differences between excitatory and inhibitory sensory information that targets the auditory SC. The superior colliculus (SC) is a midbrain structure that integrates auditory, somatosensory and visual inputs to drive orientation movements. While much is known about how visual information is processed in the superficial layers of the SC, little is known about the SC circuits in the deep layers that process auditory inputs. We therefore characterized intrinsic neuronal properties in the auditory‐recipient layer of the SC (stratum griseum profundum; SGP) and confirmed three electrophysiologically defined clusters of neurons, consistent with literature from other SC layers. To determine the types of inputs to the SGP, we expressed Channelrhodopsin‐2 in the nucleus of the brachium of the inferior colliculus (nBIC) and external cortex of the inferior colliculus (ECIC) and optically stimulated these pathways while recording from SGP neurons. Probing the connections in this manner, we described a monosynaptic excitation that additionally drives feed‐forward inhibition via circuits intrinsic to the SC. Moreover, we found a profound long‐range monosynaptic inhibition in 100% of recorded SGP neurons, a surprising finding considering that only about 15% of SGP‐projecting neurons in the nBIC/ECIC are inhibitory. Furthermore, we found spatial differences in the cell body locations as well as axon trajectories between the monosynaptic excitatory and inhibitory inputs, suggesting that these inputs may be functionally distinct. Taking this together with recent anatomical evidence suggesting an auditory excitation from the nBIC and a GABAergic multimodal inhibition from the ECIC, we propose that sensory integration in the SGP is more multifaceted than previously thought.

Short-term Synaptic Depression in the Feedforward Inhibitory Circuit in the Dorsal Lateral Geniculate Nucleus

Synaptic short-term plasticity (STP) regulates synaptic transmission in an activity-dependent manner and thereby has important roles in the signal processing in the brain. In some synapses, a presynaptic train of action potentials elicits post-synaptic potentials that gradually increase during the train (facilitation), but in other synapses, these potentials gradually decrease (depression). We studied STP in neurons in the visual thalamic relay, the dorsal lateral geniculate nucleus (dLGN). The dLGN contains two types of neurons: excitatory thalamocortical (TC) neurons, which transfer signals from retinal afferents to visual cortex, and local inhibitory interneurons, which form an inhibitory feedforward loop that regulates the thalamocortical signal transmission. The overall STP in the retino-thalamic relay is short-term depression, but the distinct kind and characteristics of the plasticity at the different types of synapses are unknown. We studied STP in the excitatory responses of interneurons to stimulation of retinal afferents, in the inhibitory responses of TC neurons to stimulation of afferents from interneurons, and in the disynaptic inhibitory responses of TC neurons to stimulation of retinal afferents. Moreover, we studied STP at the direct excitatory input to TC neurons from retinal afferents. The STP at all types of the synapses showed short-term depression. This depression can accentuate rapid changes in the stream of signals and thereby promote detectability of significant features in the sensory input. In vision, detection of edges and contours is essential for object perception, and the synaptic short-term depression in the early visual pathway provides important contributions to this detection process.

Short-Term Plasticity Combines with Excitation-Inhibition Balance to Expand Cerebellar Purkinje Cell Dynamic Range.

The balance between excitation (E) and inhibition (I) in neuronal networks controls the firing rate of principal cells through simple network organization, such as feedforward inhibitory circuits. Here, we demonstrate in male mice, that at the granule cell (GrC)-molecular layer interneuron (MLI)-Purkinje cell (PC) pathway of the cerebellar cortex, E/I balance is dynamically controlled by short-term dynamics during bursts of stimuli, shaping cerebellar output. Using a combination of electrophysiological recordings, optogenetic stimulation, and modeling, we describe the wide range of bidirectional changes in PC discharge triggered by GrC bursts, from robust excitation to complete inhibition. At high frequency (200 Hz), increasing the number of pulses in a burst (from 3 to 7) can switch a net inhibition of PC to a net excitation. Measurements of EPSCs and IPSCs during bursts and modeling showed that this feature can be explained by the interplay between short-term dynamics of the GrC-MLI-PC pathway and E/I balance impinging on PC. Our findings demonstrate that PC firing rate is highly sensitive to the duration of GrC bursts, which may define a temporal-to-rate code transformation in the cerebellar cortex.SIGNIFICANCE STATEMENT Sensorimotor information processing in the cerebellar cortex leads to the occurrence of a sequence of synaptic excitation and inhibition in Purkinje cells. Granule cells convey direct excitatory inputs and indirect inhibitory inputs to the Purkinje cells, through molecular layer interneurons, forming a feedforward inhibitory pathway. Using electrophysiological recordings, optogenetic stimulation, and mathematical modeling, we found that presynaptic short-term dynamics affect the balance between synaptic excitation and inhibition on Purkinje cells during high-frequency bursts and can reverse the sign of granule cell influence on Purkinje cell discharge when burst duration increases. We conclude that short-term dynamics may play an important role in transforming the duration of sensory inputs arriving on cerebellar granule cells into cerebellar cortical output firing rate.

A Feedforward Inhibitory Circuit Mediated by CB1-Expressing Fast-Spiking Interneurons in the Nucleus Accumbens.

The nucleus accumbens (NAc) gates motivated behaviors through the functional output of principle medium spiny neurons (MSNs), whereas dysfunctional output of NAc MSNs contributes to a variety of psychiatric disorders. Fast-spiking interneurons (FSIs) are sparsely distributed throughout the NAc, forming local feedforward inhibitory circuits. It remains elusive how FSI-based feedforward circuits regulate the output of NAc MSNs. Here, we investigated a distinct subpopulation of NAc FSIs that express the cannabinoid receptor type-1 (CB1). Using a combination of paired electrophysiological recordings and pharmacological approaches, we characterized and compared feedforward inhibition of NAc MSNs from CB1+ FSIs and lateral inhibition from recurrent MSN collaterals. We observed that CB1+ FSIs exerted robust inhibitory control over a large percentage of nearby MSNs in contrast to local MSN collaterals that provided only sparse and weak inhibitory input to their neighboring MSNs. Furthermore, CB1+ FSI-mediated feedforward inhibition was preferentially suppressed by endocannabinoid (eCB) signaling, whereas MSN-mediated lateral inhibition was unaffected. Finally, we demonstrated that CB1+ FSI synapses onto MSNs are capable of undergoing experience-dependent long-term depression in a voltage- and eCB-dependent manner. These findings demonstrated that CB1+ FSIs are a major source of local inhibitory control of MSNs and a critical component of the feedforward inhibitory circuits regulating the output of the NAc.

Dynamic balance of excitation and inhibition rapidly modulates spike probability and precision in feed-forward hippocampal circuits.

Feed-forward inhibitory (FFI) circuits are important for many information-processing functions. FFI circuit operations critically depend on the balance and timing between the excitatory and inhibitory components, which undergo rapid dynamic changes during neural activity due to short-term plasticity (STP) of both components. How dynamic changes in excitation/inhibition (E/I) balance during spike trains influence FFI circuit operations remains poorly understood. In the current study we examined the role of STP in the FFI circuit functions in the mouse hippocampus. Using a coincidence detection paradigm with simultaneous activation of two Schaffer collateral inputs, we found that the spiking probability in the target CA1 neuron was increased while spike precision concomitantly decreased during high-frequency bursts compared with a single spike. Blocking inhibitory synaptic transmission revealed that dynamics of inhibition predominately modulates the spike precision but not the changes in spiking probability, whereas the latter is modulated by the dynamics of excitation. Further analyses combining whole cell recordings and simulations of the FFI circuit suggested that dynamics of the inhibitory circuit component may influence spiking behavior during bursts by broadening the width of excitatory postsynaptic responses and that the strength of this modulation depends on the basal E/I ratio. We verified these predictions using a mouse model of fragile X syndrome, which has an elevated E/I ratio, and found a strongly reduced modulation of postsynaptic response width during bursts. Our results suggest that changes in the dynamics of excitatory and inhibitory circuit components due to STP play important yet distinct roles in modulating the properties of FFI circuits.

Rapid Feedforward Inhibition and Asynchronous Excitation Regulate Granule Cell Activity in the Mammalian Main Olfactory Bulb.

Inhibitory granule cells are involved critically in shaping odor-evoked principal neuron activity in the mammalian olfactory bulb, yet little is known about how sensory input activates granule cells. Here, we show that sensory input to the olfactory bulb evokes a barrage of asynchronous synaptic excitation and highly reliable, short-latency synaptic inhibition onto granule cells via a disynaptic feedforward inhibitory circuit involving deep short-axon cells. Feedforward inhibition attenuates local depolarization within granule cell dendritic branches, interacts with asynchronous excitation to suppress granule cell spike-timing precision, and scales in strength with excitation across different levels of sensory input to normalize granule cell firing rates.

GABAB receptor-mediated feed-forward circuit dysfunction in the mouse model of fragile X syndrome.

Cortico-hippocampal feed-forward circuits formed by the temporoammonic (TA) pathway exhibit a marked increase in excitation/inhibition ratio and abnormal spike modulation functions in Fmr1 knock-out (KO) mice. Inhibitory, but not excitatory, synapse dysfunction underlies cortico-hippocampal feed-forward circuit abnormalities in Fmr1 KO mice. GABA release is reduced in TA-associated inhibitory synapses of Fmr1 KO mice in a GABAB receptor-dependent manner. Inhibitory synapse and feed-forward circuit defects are mediated predominately by presynaptic GABAB receptor signalling in the TA pathway of Fmr1 KO mice. GABAB receptor-mediated inhibitory synapse defects are circuit-specific and are not observed in the Schaffer collateral pathway-associated inhibitory synapses in stratum radiatum. Circuit hyperexcitability has been implicated in neuropathology of fragile X syndrome, the most common inheritable cause of intellectual disability. Yet, how canonical unitary circuits are affected in this disorder remains poorly understood. Here, we examined this question in the context of the canonical feed-forward inhibitory circuit formed by the temporoammonic (TA) branch of the perforant path, the major cortical input to the hippocampus. TA feed-forward circuits exhibited a marked increase in excitation/inhibition ratio and major functional defects in spike modulation tasks in Fmr1 knock-out (KO) mice, a fragile X mouse model. Changes in feed-forward circuits were caused specifically by inhibitory, but not excitatory, synapse defects. TA-associated inhibitory synapses exhibited increase in paired-pulse ratio and in the coefficient of variation of IPSPs, consistent with decreased GABA release probability. TA-associated inhibitory synaptic transmission in Fmr1 KO mice was also more sensitive to inhibition of GABAB receptors, suggesting an increase in presynaptic GABAB receptor (GABAB R) signalling. Indeed, the differences in inhibitory synaptic transmission between Fmr1 KO and wild-type (WT) mice were eliminated by a GABAB R antagonist. Inhibition of GABAB Rs or selective activation of presynaptic GABAB Rs also abolished the differences in the TA feed-forward circuit properties between Fmr1 KO and WT mice. These GABAB R-mediated defects were circuit-specific and were not observed in the Schaffer collateral pathway-associated inhibitory synapses. Our results suggest that the inhibitory synapse dysfunction in the cortico-hippocampal pathway of Fmr1 KO mice causes hyperexcitability and feed-forward circuit defects, which are mediated in part by a presynaptic GABAB R-dependent reduction in GABA release.