The Anatomy and Physiology of Claustrum-Cortex Interactions.

The claustrum is one of the most widely connected regions of the forebrain, yet its function has remained obscure, largely due to the experimentally challenging nature of targeting this small, thin, and elongated brain area. However, recent advances in molecular techniques have enabled the anatomy and physiology of the claustrum to be studied with the spatiotemporal and cell type-specific precision required to eventually converge on what this area does. Here we review early anatomical and electrophysiological results from cats and primates, as well as recent work in the rodent, identifying the connectivity, cell types, and physiological circuit mechanisms underlying the communication between the claustrum and the cortex. The emerging picture is one in which the rodent claustrum is closely tied to frontal/limbic regions and plays a role in processes, such as attention, that are associated with these areas.

Excitation and Inhibition Delays within a Feedforward Inhibitory Pathway Modulate Cerebellar Purkinje Cell Output in Mice.

The cerebellar cortex computes sensorimotor information from many brain areas through a feedforward inhibitory (FFI) microcircuit between the input stage, the granule cell (GC) layer, and the output stage, the Purkinje cells (PCs). Although in other brain areas FFI underlies a precise excitation versus inhibition temporal correlation, recent findings in the cerebellum highlighted more complex behaviors at GC-molecular layer interneuron (MLI)-PC pathway. To dissect the temporal organization of this cerebellar FFI pathway, we combined ex vivo patch-clamp recordings of PCs in male mice with a viral-based strategy to express Channelrhodopsin2 in a subset of mossy fibers (MFs), the major excitatory inputs to GCs. We show that although light-mediated MF activation elicited pairs of excitatory and inhibitory postsynaptic currents in PCs, excitation (E) from GCs and inhibition (I) from MLIs reached PCs with a wide range of different temporal delays. However, when GCs were directly stimulated, a low variability in E/I delays was observed. Our results demonstrate that in many recordings MF stimulation recruited different groups of GCs that trigger E and/or I, and expanded PC temporal synaptic integration. Finally, using a computational model of the FFI pathway, we showed that this temporal expansion could strongly influence how PCs integrate GC inputs. Our findings show that specific E/I delays may help PCs encoding specific MF inputs.SIGNIFICANCE STATEMENT Sensorimotor information is conveyed to the cerebellar cortex by mossy fibers. Mossy fiber inputs activate granule cells that excite molecular interneurons and Purkinje cells, the sole output of the cerebellar cortex, leading to a sequence of synaptic excitation and inhibition in Purkinje cells, thus defining a feedforward inhibitory pathway. Using electrophysiological recordings, optogenetic stimulation, and mathematical modeling, we demonstrated that different groups of granule cells can elicit synaptic excitation and inhibition with various latencies onto Purkinje cells. This temporal variability controls how granule cells influence Purkinje cell discharge and may support temporal coding in the cerebellar cortex.

Molecular Mechanisms Underlying the Generation of Absence Seizures: Identification of Potential Targets for Therapeutic Intervention.

Understanding the molecular mechanisms underlying the generation of absence seizures is crucial for developing effective, patient-specific treatments for childhood absence epilepsy (CAE). Currently, one-third of patients remain refractive to the antiseizure medications (ASMs), previously called antiepileptic drugs (AEDs), available to treat CAE. Additionally, these ASMs often produce serious side effects and can even exacerbate symptoms in some patients. Determining the precise cellular and molecular mechanisms directly responsible for causing this type of epilepsy has proven challenging as they appear to be complex and multifactorial in patients with different genetic backgrounds. Aberrant neuronal activity in CAE may be caused by several mechanisms that are not fully understood. Thus, dissecting the causal factors that could be targeted in the development of precision medicines without side effects remains a high priority and the ultimate goal in this field of epilepsy research. The aim of this review is to highlight our current understanding of potential causative mechanisms for absence seizure generation, based on the latest research using cutting-edge technologies. This information will be important for identifying potential targets for future therapeutic intervention.

Noradrenergic Signaling Disengages Feedforward Transmission in the Nucleus Accumbens Shell.

The nucleus accumbens shell (NAcSh) receives extensive monoaminergic input from multiple midbrain structures. However, little is known how norepinephrine (NE) modulates NAc circuit dynamics. Using a dynamic electrophysiological approach with optogenetics, pharmacology, and drugs acutely restricted by tethering (DART), we explored microcircuit-specific neuromodulatory mechanisms recruited by NE signaling in the NAcSh of parvalbumin (PV)-specific reporter mice. Surprisingly, NE had little direct effect on modulation of synaptic input at medium spiny projection neurons (MSNs). In contrast, we report that NE transmission selectively modulates glutamatergic synapses onto PV-expressing fast-spiking interneurons (PV-INs) by recruiting postsynaptically-localized α2-adrenergic receptors (ARs). The synaptic effects of α2-AR activity decrease PV-IN-dependent feedforward inhibition onto MSNs evoked via optogenetic stimulation of cortical afferents to the NAcSh. These findings provide insight into a new circuit motif in which NE has a privileged line of communication to tune feedforward inhibition in the NAcSh.SIGNIFICANCE STATEMENT The nucleus accumbens (NAc) directs reward-related motivational output by integrating glutamatergic input with diverse neuromodulatory input from monoamine centers. The present study reveals a synapse-specific regulatory mechanism recruited by norepinephrine (NE) signaling within parvalbumin-expressing interneuron (PV-IN) feedforward inhibitory microcircuits. PV-IN-mediated feedforward inhibition in the NAc is instrumental in coordinating NAc output by synchronizing the activity of medium spiny projection neurons (MSNs). By negatively regulating glutamatergic transmission onto PV-INs via α2-adrenergic receptors (ARs), NE diminishes feedforward inhibition onto MSNs to promote NAc output. These findings elucidate previously unknown microcircuit mechanisms recruited by the historically overlooked NE system in the NAc.

CDKL5 Deficiency Augments Inhibitory Input into the Dentate Gyrus That Can Be Reversed by Deep Brain Stimulation.

Cognitive impairment is a core feature of cyclin-dependent kinase-like 5 (CDKL5) deficiency, a neurodevelopmental disorder characterized by early epileptic seizures, intellectual disability, and autistic behaviors. Although loss of CDKL5 affects a number of molecular pathways, very little has been discovered about the physiological effects of these changes on the neural circuitry. We therefore studied synaptic plasticity and local circuit activity in the dentate gyrus of both Cdkl5-/y and Cdkl5+/- mutant mice. We found that CDKL5 haploinsufficiency in both male and female mice impairs hippocampus-dependent learning and memory in multiple tasks. In vivo, loss of CDKL5 reduced LTP of the perforant path to the dentate gyrus and augmented feedforward inhibition in this pathway; ex vivo experiments confirmed that excitatory/inhibitory input into the dentate gyrus is skewed toward inhibition. Injecting the GABAergic antagonist gabazine into the dentate improved contextual fear memory in Cdkl5-/y mice. Finally, chronic forniceal deep brain stimulation rescued hippocampal memory deficits, restored synaptic plasticity, and relieved feedforward inhibition in Cdkl5+/- mice. These results indicate that CDKL5 is important for maintaining proper dentate excitatory/inhibitory balance, with consequences for hippocampal memory.SIGNIFICANCE STATEMENT Cognitive impairment is a core feature of cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder. Although CDKL5 deficiency has been found to affect a number of molecular pathways, little is known about its physiological effects on the neural circuitry. We find that CDKL5 loss reduces hippocampal synaptic plasticity and augments feedforward inhibition in the perforant path to the dentate gyrus in vivo in Cdkl5 mutant mice. Chronic forniceal deep brain stimulation rescued hippocampal memory deficits, restored synaptic plasticity, and relieved feedforward inhibition in Cdkl5+/- mice, as it had previously done with Rett syndrome mice, suggesting that such stimulation may be useful for other neurodevelopmental disorders.

A model of lateral interactions as the origin of multiwhisker receptive fields in rat barrel cortex.

While cells within barrel cortex respond primarily to deflections of their principal whisker (PW), they also exhibit responses to non-principal, or adjacent, whiskers (AWs), albeit responses with diminished amplitudes and longer latencies. The origin of multiwhisker receptive fields of barrel cells remains a point of controversy within the experimental literature, with three contending possibilities: (i) barrel cells inherit their AW responses from the AW responses of thalamocortical (TC) cells within their aligned barreloid; (ii) the axons of TC cells within a barreloid ramify to innervate multiple barrels, rather than only terminating within their aligned barrel; (iii) lateral intracortical transmission between barrels conveys AW responsivity to barrel cells. In this work, we develop a detailed, biologically plausible model of multiple barrels in order to examine possibility (iii); in order to isolate the dynamics that possibility (iii) entails, we incorporate lateral connections between barrels while assuming that TC cells respond only to their PW and that TC cell axons are confined to their home barrel. We show that our model is capable of capturing a broad swath of experimental observations on multiwhisker receptive field dynamics within barrels, and we compare and contrast the dynamics of this model with model dynamics from prior work in which employ a similar general modeling strategy to examine possibility (i).

A model of feedforward, global, and lateral inhibition in the locust visual system predicts responses to looming stimuli.

Detection of looming obstacles is a vital task for both natural and artificial systems. Locusts possess a visual nervous system with an extensively studied obstacle detection pathway, culminating in the lobula giant movement detector (LGMD) neuron. While numerous models of this system exist, none to date have incorporated recent data on the anatomy and function of feedforward and global inhibitory systems in the input network of the LGMD. Moreover, the possibility that global and lateral inhibition shape the feedforward inhibitory signals to the LGMD has not been investigated. To address these points, a novel model of feedforward inhibitory neurons in the locust optic lobe was developed based on the recent literature. This model also incorporated global and lateral inhibition into the afferent network of these neurons, based on their observed behaviour in existing data and the posited role of these mechanisms in the inputs to the LGMD. Tests with the model showed that it accurately replicates the behaviour of feedforward inhibitory neurons in locusts; the model accurately coded for stimulus angular size in an overall linear fashion, with decreasing response saturation and increasing linearity as stimulus size increased or approach velocity decreased. The model also exhibited only phasic responses to the appearance of a grating, along with sustained movement by it at constant speed. By observing the effects of altering inhibition schemes on these responses, it was determined that global inhibition serves primarily to normalize growing excitation as collision approaches, and keeps coding for subtense angle linear. Lateral inhibition was determined to suppress tonic responses to wide-field stimuli translating at constant speed. Based on these features being shared with characterizations of the LGMD input network, it was hypothesized that the feedforward inhibitory neurons and the LGMD share the same excitatory afferents; this necessitates further investigation.

Interplay of Entorhinal Input and Local Inhibitory Network in the Hippocampus at the Origin of Slow Inhibition in Granule Cells.

Neuronal activity from the entorhinal cortex propagates through the perforant path (PP) to the molecular layer of the dentate gyrus (DG) where information is filtered and converted into sparse hippocampal code. Nearly simultaneous signaling to both granule cells (GC) and local interneurons (INs) engages network interactions that will modulate input integration and output generation. When triggered, GABA release from interneurons counteracts the glutamatergic signals of PP terminals, scaling down the overall DG activation. Inhibition occurs at fast or slow timescales depending on the activation of ionotropic GABAA-R or metabotropic GABAB-R. Although postsynaptic GABAA and GABAB-R differ in their location at the synapse, mixed GABAA/B-R IPSPs can also occur. Here we describe a slow inhibition mechanism in mouse GCs recorded from either sex, mediated by GABAA/B-R in combination with metabotropic glutamate receptors. Short burst PP stimulation in the gamma frequency range lead to a long-lasting hyperpolarization (LLH) of the GCs with a duration that exceeds GABAB-R IPSPs. As a result, LLH alters GC firing patterns and the responses to concomitant excitatory signals are also affected. Synaptic recruitment of feedforward inhibition and subsequent GABA release from interneurons, also successfully trigger mixed GABA responses in GCs. Together these results suggest that slow inhibition through LLH leads to reduced excitability of GCs during entorhinal input integration. The implication of LLH in regulation of neuronal excitability suggests it also contributes to the sparse population coding in DG.SIGNIFICANCE STATEMENT Our study describes a long-lasting hyperpolarization (LLH) in hippocampal granule cells. We used whole-cell patch-clamp recordings and an optogenetic approach to characterize this event. LLH is a slow inhibitory mechanism that occurs following the stimulation of the perforant pathway in the molecular layer of the dentate gyrus. We found that it is mediated via postsynaptic ionotropic and metabotropic GABA and metabotropic glutamate receptors. The duration of LLH exceeds previously described IPSPs mediated by any of these receptors. The activation of LLH requires presynaptic gamma frequency bursts and recruitment of the local feedforward inhibition. LLH defines prolonged periods of low excitability of GCs and a restrained neuronal discharge. Our results suggest that LLH can contribute to sparse activation of GCs.

Pathway-Specific Drive of Cerebellar Golgi Cells Reveals Integrative Rules of Cortical Inhibition.

Cerebellar granule cells (GrCs) constitute over half of all neurons in the vertebrate brain and are proposed to decorrelate convergent mossy fiber (MF) inputs in service of learning. Interneurons within the GrC layer, Golgi cells (GoCs), are the primary inhibitors of this vast population and therefore play a major role in influencing the computations performed within the layer. Despite this central function for GoCs, few studies have directly examined how GoCs integrate inputs from specific afferents, which vary in density to regulate GrC population activity. We used a variety of methods in mice of either sex to study feedforward inhibition recruited by identified MFs, focusing on features that would influence integration by GrCs. Comprehensive 3D reconstruction and quantification of GoC axonal boutons revealed tightly clustered boutons that focus feedforward inhibition in the neighborhood of GoC somata. Acute whole-cell patch-clamp recordings from GrCs in brain slices showed that, despite high GoC bouton density, fast phasic inhibition was very sparse relative to slow spillover mediated inhibition. Dynamic-clamp simulating inhibition combined with optogenetic MF activation at moderate rates supported a predominant role of slow spillover mediated inhibition in reducing GrC activity. Whole-cell recordings from GoCs revealed a role for the density of active MFs in preferentially driving them. Thus, our data provide empirical confirmation of predicted rules by which MFs activate GoCs to regulate GrC activity levels.SIGNIFICANCE STATEMENT A unifying framework in neural circuit analysis is identifying circuit motifs that subserve common computations. Wide-field inhibitory interneurons globally inhibit neighbors and have been studied extensively in the insect olfactory system and proposed to serve pattern separation functions. Cerebellar Golgi cells (GoCs), a type of mammalian wide-field inhibitory interneuron observed in the granule cell layer, are well suited to perform normalization or pattern separation functions, but the relationship between spatial characteristics of input patterns to GoC-mediated inhibition has received limited attention. This study provides unprecedented quantitative structural details of GoCs and identifies a role for population input activity levels in recruiting inhibition using in vitro electrophysiology and optogenetics.

Pedunculopontine Glutamatergic Neurons Provide a Novel Source of Feedforward Inhibition in the Striatum by Selectively Targeting Interneurons.

The main excitatory inputs to the striatum arising from the cortex and the thalamus innervate both striatal spiny projection neurons and interneurons. These glutamatergic inputs to striatal GABAergic interneurons have been suggested to regulate the spike timing of striatal projection neurons via feedforward inhibition. Understanding how different excitatory inputs are integrated within the striatal circuitry and how they regulate striatal output is crucial for understanding basal ganglia function and related behaviors. Here, using VGLUT2 mice from both sexes, we report the existence of a glutamatergic projection from the mesencephalic locomotor region to the striatum that avoids the spiny neurons and selectively innervates interneurons. Specifically, optogenetic activation of glutamatergic axons from the pedunculopontine nucleus induced monosynaptic excitation in most recorded striatal cholinergic interneurons and GABAergic fast-spiking interneurons. Optogenetic stimulation in awake head-fixed mice consistently induced an increase in the firing rate of putative cholinergic interneurons and fast-spiking interneurons. In contrast, this stimulation did not induce excitatory responses in spiny neurons but rather disynaptic inhibitory responses ex vivo and a decrease in their firing rate in vivo, suggesting a feedforward mechanism mediating the inhibition of spiny projection neurons through the selective activation of striatal interneurons. Furthermore, unilateral stimulation of pedunculopontine nucleus glutamatergic axons in the striatum induced ipsilateral head rotations consistent with the inhibition of striatal output neurons. Our results demonstrate the existence of a unique interneuron-specific midbrain glutamatergic input to the striatum that exclusively recruits feedforward inhibition mechanisms.SIGNIFICANCE STATEMENT Glutamatergic inputs to the striatum have been shown to target both striatal projection neurons and interneurons and have been proposed to regulate spike timing of the projection neurons in part through feedforward inhibition. Here, we reveal the existence of a midbrain source of glutamatergic innervation to the striatum, originating in the pedunculopontine nucleus. Remarkably, this novel input selectively targets striatal interneurons, avoiding the projection neurons. Furthermore, we show that this selective innervation of interneurons can regulate the firing of the spiny projection neurons and inhibit the striatal output via feedforward inhibition. Together, our results describe a unique source of excitatory innervation to the striatum which selectively recruits feedforward inhibition of spiny neurons without any accompanying excitation.

Heterosynaptic GABAB Receptor Function within Feedforward Microcircuits Gates Glutamatergic Transmission in the Nucleus Accumbens Core.

Complex circuit interactions within the nucleus accumbens (NAc) facilitate goal-directed behavior. Medium spiny neurons (MSNs) mediate NAc output by projecting to functionally divergent brain regions, a property conferred, in part, by the differential projection patterns of D1- and D2 dopamine receptor-expressing MSNs. Glutamatergic afferents to the NAc direct MSN output by recruiting feedforward inhibitory microcircuits comprised of parvalbumin (PV)-expressing interneurons (INs). Furthermore, the GABAB heteroreceptor (GABABR), a Gi/o-coupled G-protein-coupled receptor, is expressed at glutamatergic synapses throughout the mesolimbic network, yet its physiological context and synaptic mechanism within the NAc remains unknown. Here, we explored GABABR function at glutamatergic synapses within PV-IN-embedded microcircuits in the NAc core of male mice. We found that GABABR is expressed presynaptically and recruits a noncanonical signaling mechanism to reduce glutamatergic synaptic efficacy at D1(+) and D1(-) (putative D2) MSN subtypes. Furthermore, PV-INs, a robust source of neuronal GABA in the NAc, heterosynaptically target GABABR to selectively modulate glutamatergic transmission onto D1(+) MSNs. These findings elucidate a new mechanism of feedforward inhibition and refine mechanisms by which GABAB heteroreceptors modulate mesolimbic circuit function.SIGNIFICANCE STATEMENT Glutamatergic transmission in the nucleus accumbens (NAc) critically contributes to goal-directed behaviors. However, intrinsic microcircuit mechanisms governing the integration of these synapses remain largely unknown. Here, we show that parvalbumin-expressing interneurons within feedforward microcircuits heterosynaptically target GABAB heteroreceptors (GABABR) on glutamate terminals. Activation of presynaptically-expressed GABABR decreases glutamatergic synaptic strength by engaging a non-canonical signaling pathway that interferes with vesicular exocytotic release machinery. These findings offer mechanistic insight into the role of GABAB heteroreceptors within reward circuitry, elucidate a novel arm to feedforward inhibitory networks, and inform the growing use of GABABR-selective pharmacotherapy for various motivational disorders, including addiction, major depressive disorder, and autism (Cousins et al., 2002; Kahn et al., 2009; Jacobson et al., 2018; Stoppel et al., 2018; Pisansky et al., 2019).

Computational analysis of NIRS and BOLD signal from neurovascular coupling with three neuron-system feedforward inhibition network.

Several neurological disorders occur due to hypoxic condition in brain arising from impairment of cerebral functionality, which can be controlled by neural stimulation driven vasoactive response mediated through biological response in astrocyte, a phenomenon known as neurovascular coupling. Brain can adjust with the problem of hypoxic condition by causing vasodilation with the help of this mechanism. To deduce the mechanism behind vasodilation of blood vessel caused by neuronal stimulus, current study articulates a mathematical model involving neuronal system feedforward inhibition network model (FFI) with two other functional components of neurovascular coupling, i.e. astrocyte and smooth muscle cell lining blood vessel. This study includes the neural inhibition network system where glutamatergic pyramidal neuron and GABAergic interneuron act antagonistically with each other. The proposed model successfully includes the implication of the inhibition system to design mathematical model for neurovascular coupling. Result of the proposed model shows that the increase in neuronal stimulus from 20 to 60 µA/cm2 has the ability to increase the vasodilatory activity of blood tissue vasculature. Oxygenation level and hemodynamic response due to input synaptic stimulation has been calculated by regional cerebral oxygenation level (rS02) and blood oxygen level dependent (BOLD) imaging signal which supports vasodilation of blood vessel with increase in synaptic input stimulus.

Target Interneuron Preference in Thalamocortical Pathways Determines the Temporal Structure of Cortical Responses.

Sensory processing relies on fast detection of changes in environment, as well as integration of contextual cues over time. The mechanisms by which local circuits of the cerebral cortex simultaneously perform these opposite processes remain obscure. Thalamic "specific" nuclei relay sensory information, whereas "nonspecific" nuclei convey information on the environmental and behavioral contexts. We expressed channelrhodopsin in the ventrobasal specific (sensory) or the rhomboid nonspecific (contextual) thalamic nuclei. By selectively activating each thalamic pathway, we found that nonspecific inputs powerfully activate adapting (slow-responding) interneurons but weakly connect fast-spiking interneurons, whereas specific inputs exhibit opposite interneuron preference. Specific inputs thereby induce rapid feedforward inhibition that limits response duration, whereas, in the same cortical area, nonspecific inputs elicit delayed feedforward inhibition that enables lasting recurrent excitation. Using a mean field model, we confirm that cortical response dynamics depends on the type of interneuron targeted by thalamocortical inputs and show that efficient recruitment of adapting interneurons prolongs the cortical response and allows the summation of sensory and contextual inputs. Hence, target choice between slow- and fast-responding inhibitory neurons endows cortical networks with a simple computational solution to perform both sensory detection and integration.

Cross-scale effects of neural interactions during human neocortical seizure activity.

Small-scale neuronal networks may impose widespread effects on large network dynamics. To unravel this relationship, we analyzed eight multiscale recordings of spontaneous seizures from four patients with epilepsy. During seizures, multiunit spike activity organizes into a submillimeter-sized wavefront, and this activity correlates significantly with low-frequency rhythms from electrocorticographic recordings across a 10-cm-sized neocortical network. Notably, this correlation effect is specific to the ictal wavefront and is absent interictally or from action potential activity outside the wavefront territory. To examine the multiscale interactions, we created a model using a multiscale, nonlinear system and found evidence for a dual role for feedforward inhibition in seizures: while inhibition at the wavefront fails, allowing seizure propagation, feedforward inhibition of the surrounding centimeter-scale networks is activated via long-range excitatory connections. Bifurcation analysis revealed that distinct dynamical pathways for seizure termination depend on the surrounding inhibition strength. Using our model, we found that the mesoscopic, local wavefront acts as the forcing term of the ictal process, while the macroscopic, centimeter-sized network modulates the oscillatory seizure activity.

Single Bursts of Individual Granule Cells Functionally Rearrange Feedforward Inhibition.

The sparse single-spike activity of dentate gyrus granule cells (DG GCs) is punctuated by occasional brief bursts of 3-7 action potentials. It is well-known that such presynaptic bursts in individual mossy fibers (MFs; axons of granule cells) are often able to discharge postsynaptic CA3 pyramidal cells due to powerful short-term facilitation. However, what happens in the CA3 network after the passage of a brief MF burst, before the arrival of the next burst or solitary spike, is not understood. Because MFs innervate significantly more CA3 interneurons than pyramidal cells, we focused on unitary MF responses in identified interneurons in the seconds-long postburst period, using paired recordings in rat hippocampal slices. Single bursts as short as 5 spikes in <30 ms in individual presynaptic MFs caused a sustained, large increase (tripling) in the amplitude of the unitary MF-EPSCs for several seconds in ivy, axo-axonic/chandelier and basket interneurons. The postburst unitary MF-EPSCs in these feedforward interneurons reached amplitudes that were even larger than the MF-EPSCs during the bursts in the same cells. In contrast, no comparable postburst enhancement of MF-EPSCs could be observed in pyramidal cells or nonfeedforward interneurons. The robust postburst increase in MF-EPSCs in feedforward interneurons was associated with significant shortening of the unitary synaptic delay and large downstream increases in disynaptic IPSCs in pyramidal cells. These results reveal a new cell type-specific plasticity that enables even solitary brief bursts in single GCs to powerfully enhance inhibition at the DG-CA3 interface in the seconds-long time-scales of interburst intervals.SIGNIFICANCE STATEMENT The hippocampal formation is a brain region that plays key roles in spatial navigation and learning and memory. The first stage of information processing occurs in the dentate gyrus, where principal cells are remarkably quiet, discharging low-frequency single action potentials interspersed with occasional brief bursts of spikes. Such bursts, in particular, have attracted a lot of attention because they appear to be critical for efficient coding, storage, and recall of information. We show that single bursts of a few spikes in individual granule cells result in seconds-long potentiation of excitatory inputs to downstream interneurons. Thus, while it has been known that bursts powerfully discharge ("detonate") hippocampal excitatory cells, this study clarifies that they also regulate inhibition during the interburst intervals.

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.

GABAergic Local Interneurons Shape Female Fruit Fly Response to Mating Songs.

Many animals use acoustic signals to attract a potential mating partner. In fruit flies (Drosophila melanogaster), the courtship pulse song has a species-specific interpulse interval (IPI) that activates mating. Although a series of auditory neurons in the fly brain exhibit different tuning patterns to IPIs, it is unclear how the response of each neuron is tuned. Here, we studied the neural circuitry regulating the activity of antennal mechanosensory and motor center (AMMC)-B1 neurons, key secondary auditory neurons in the excitatory neural pathway that relay song information. By performing Ca2+ imaging in female flies, we found that the IPI selectivity observed in AMMC-B1 neurons differs from that of upstream auditory sensory neurons [Johnston's organ (JO)-B]. Selective knock-down of a GABAA receptor subunit in AMMC-B1 neurons increased their response to short IPIs, suggesting that GABA suppresses AMMC-B1 activity at these IPIs. Connection mapping identified two GABAergic local interneurons that synapse with AMMC-B1 and JO-B. Ca2+ imaging combined with neuronal silencing revealed that these local interneurons, AMMC-LN and AMMC-B2, shape the response pattern of AMMC-B1 neurons at a 15 ms IPI. Neuronal silencing studies further suggested that both GABAergic local interneurons suppress the behavioral response to artificial pulse songs in flies, particularly those with a 15 ms IPI. Altogether, we identified a circuit containing two GABAergic local interneurons that affects the temporal tuning of AMMC-B1 neurons in the song relay pathway and the behavioral response to the courtship song. Our findings suggest that feedforward inhibitory pathways adjust the behavioral response to courtship pulse songs in female flies.SIGNIFICANCE STATEMENT To understand how the brain detects time intervals between sound elements, we studied the neural pathway that relays species-specific courtship song information in female Drosophila melanogaster We demonstrate that the signal transmission from auditory sensory neurons to key secondary auditory neurons antennal mechanosensory and motor center (AMMC)-B1 is the first-step to generate time interval selectivity of neurons in the song relay pathway. Two GABAergic local interneurons are suggested to shape the interval selectivity of AMMC-B1 neurons by receiving auditory inputs and in turn providing feedforward inhibition onto AMMC-B1 neurons. Furthermore, these GABAergic local interneurons suppress the song response behavior in an interval-dependent manner. Our results provide new insights into the neural circuit basis to adjust neuronal and behavioral responses to a species-specific communication sound.

Rapid Disinhibition by Adjustment of PV Intrinsic Excitability during Whisker Map Plasticity in Mouse S1.

Rapid plasticity of layer (L) 2/3 inhibitory circuits is an early step in sensory cortical map plasticity, but its cellular basis is unclear. We show that, in mice of either sex, 1 d whisker deprivation drives the rapid loss of L4-evoked feedforward inhibition and more modest loss of feedforward excitation in L2/3 pyramidal (PYR) cells, increasing the excitation-inhibition conductance ratio. Rapid disinhibition was due to reduced L4-evoked spiking by L2/3 parvalbumin (PV) interneurons, caused by reduced PV intrinsic excitability. This included elevated PV spike threshold, which is associated with an increase in low-threshold, voltage-activated delayed rectifier (presumed Kv1) and A-type potassium currents. Excitatory synaptic input and unitary inhibitory output of PV cells were unaffected. Functionally, the loss of feedforward inhibition and excitation was precisely coordinated in L2/3 PYR cells, so that peak feedforward synaptic depolarization remained stable. Thus, the rapid plasticity of PV intrinsic excitability offsets early weakening of excitatory circuits to homeostatically stabilize synaptic potentials in PYR cells of sensory cortex.SIGNIFICANCE STATEMENT Inhibitory circuits in cerebral cortex are highly plastic, but the cellular mechanisms and functional importance of this plasticity are incompletely understood. We show that brief (1 d) sensory deprivation rapidly weakens parvalbumin (PV) inhibitory circuits by reducing the intrinsic excitability of PV neurons. This involved a rapid increase in voltage-gated potassium conductances that control near-threshold spiking excitability. Functionally, the loss of PV-mediated feedforward inhibition in L2/3 pyramidal cells was precisely balanced with the separate loss of feedforward excitation, resulting in a net homeostatic stabilization of synaptic potentials. Thus, rapid plasticity of PV intrinsic excitability implements network-level homeostasis to stabilize synaptic potentials in sensory cortex.

Hippocampal-Evoked Feedforward Inhibition in the Nucleus Accumbens.

The nucleus accumbens (NAc) is critical for motivated behavior and is rewired following exposure to drugs of abuse. Medium spiny neurons (MSNs) in the NAc express either D1 or D2 receptors and project to distinct downstream targets. Differential activation of these MSNs depends on both excitation from long-range inputs and inhibition via the local circuit. Assessing how long-range excitatory inputs engage inhibitory circuitry is therefore important for understanding NAc function. Here, we use slice electrophysiology and optogenetics to study ventral hippocampal (vHPC)-evoked feedforward inhibition in the NAc of male and female mice. We find that vHPC-evoked excitation is stronger at D1+ than D1- MSNs, whereas inhibition is unbiased at the two cell types. vHPC inputs contact both parvalbumin-positive (PV+) and somatostatin-positive (SOM+) interneurons, but PV+ cells are preferentially activated. Moreover, suppressing PV+ interneurons indicates they are primarily responsible for vHPC-evoked inhibition. Finally, repeated cocaine exposure alters the excitation of D1+ and D1- MSNs, without concomitant changes to inhibition, shifting the excitation/inhibition balance. Together, our results highlight the contributions of multiple interneuron populations to feedforward inhibition in the NAc. Moreover, they demonstrate that inhibition provides a stable backdrop on which drug-evoked changes to excitation occur within this circuit.SIGNIFICANCE STATEMENT Given the importance of the nucleus accumbens (NAc) in reward learning and drug-seeking behaviors, it is critical to understand what controls the activity of cells in this region. While excitatory inputs to projection neurons in the NAc have been identified, it is unclear how the local inhibitory network becomes engaged. Here, we identify a sparse population of interneurons responsible for feedforward inhibition evoked by ventral hippocampal input and characterize their connections within the NAc. We also demonstrate that the balance of excitation and inhibition that projection neurons experience is altered by exposure to cocaine. Together, this work provides insight into the fundamental circuitry of this region as well as the effects of drugs of abuse.

The impact of silencing feed-forward parvalbumin-expressing inhibitory interneurons in the cortico-thalamocortical network on seizure generation and behaviour.

Feed-forward inhibition (FFI) is an essential mechanism within the brain, to regulate neuronal firing and prevent runaway excitation. In the cortico-thalamocortical (CTC) network, fast spiking parvalbumin-expressing (PV+) inhibitory interneurons regulate the firing of pyramidal cells in the cortex and relay neurons in the thalamus. PV+ interneuron dysfunction has been implicated in several neurological disorders, including epilepsy. Previously, we demonstrated that loss of excitatory AMPA-receptors, specifically at synapses on PV+ interneurons in CTC feedforward microcircuits, occurs in the stargazer mouse model of absence epilepsy. These mice present with absence seizures characterized by spike and wave discharges (SWDs) on electroencephalogram (EEG) and concomitant behavioural arrest, similar to childhood absence epilepsy. The aim of the current study was to investigate the impact of loss of FFI within the CTC on absence seizure generation and behaviour using new Designer Receptor Exclusively Activated by Designer Drug (DREADD) technology. We crossed PV-Cre mice with Cre-dependent hM4Di DREADD strains of mice, which allowed Cre-recombinase-mediated restricted expression of inhibitory Gi-DREADDs in PV+ interneurons. We then tested the impact of global and focal (within the CTC network) silencing of PV+ interneurons. CNO mediated silencing of all PV+ interneurons by intraperitoneal injection caused the impairment of motor control, decreased locomotion and increased anxiety in a dose-dependent manner. Such silencing generated pathological oscillations similar to absence-like seizures. Focal silencing of PV+ interneurons within cortical or thalamic feedforward microcircuits, induced SWD-like oscillations and associated behavioural arrest. Epileptiform activity on EEG appeared significantly sooner after focal injection compared to peripheral injection of CNO. However, the mean duration of each oscillatory burst and spike frequency was similar, irrespective of mode of CNO delivery. No significant changes were observed in vehicle-treated or non-DREADD wild-type control animals. These data suggest that dysfunctional feed-forward inhibition in CTC microcircuits may be an important target for future therapy strategies for some patients with absence seizures. Additionally, silencing of PV+ interneurons in other brain regions may contribute to anxiety related neurological and psychiatric disorders.