Activity Of Inhibitory Interneurons Research Articles

A Model-Driven Meta-Analysis Supports the Emerging Consensus View that Inhibitory Neurons Dominate BOLD-fMRI Responses.

Functional magnetic resonance imaging (fMRI) is a pivotal tool for mapping neuronal activity in the brain. Traditionally, the observed hemodynamic changes are assumed to reflect the activity of the most common neuronal type: excitatory neurons. In contrast, recent experiments, using optogenetic techniques, suggest that the fMRI-signal instead reflects the activity of inhibitory interneurons. However, these data paint a complex picture, with numerous regulatory interactions, and where the different experiments display many qualitative differences. It is therefore not trivial how to quantify the relative contributions of the different cell types and to combine all observations into a unified theory. To address this, we present a new model-driven meta-analysis, which provides a unified and quantitative explanation for all data. This model-driven analysis allows for quantification of the relative contribution of different cell types: the contribution to the BOLD-signal from the excitatory cells is <20 % and 50-80 % comes from the interneurons. Our analysis also provides a mechanistic explanation for the observed experiment-to-experiment differences, e.g. a biphasic vascular response dependent on different stimulation intensities and an emerging secondary post-stimulation peak during longer stimulations. In summary, our study provides a new, emerging consensus-view supporting the larger role of interneurons in fMRI.

Local stimulation of pyramidal neurons in deep cortical layers of anesthetized rats enhances cortical visual information processing

In the primary visual cortex area V1 activation of inhibitory interneurons, which provide negative feedback for excitatory pyramidal neurons, can improve visual response reliability and orientation selectivity. Moreover, optogenetic activation of one class of interneurons, parvalbumin (PV) positive cells, reduces the receptive field (RF) width. These data suggest that in V1 the negative feedback improves visual information processing. However, according to information theory, noise can limit information content in a signal, and to the best of our knowledge, in V1 signal-to-noise ratio (SNR) has never been estimated following either pyramidal or inhibitory neuron activation. Therefore, we optogenetically activated pyramidal or PV neurons in the deep layers of cortical area V1 and measured the SNR and RF area in nearby pyramidal neurons. Activation of pyramidal or PV neurons increased the SNR by 267% and 318%, respectively, and reduced the RF area to 60.1% and 77.5%, respectively, of that of the control. A simple integrate-and-fire neuron model demonstrated that an improved SNR and a reduced RF area can increase the amount of information encoded by neurons. We conclude that in V1 activation of pyramidal neurons improves visual information processing since the location of the visual stimulus can be pinpointed more accurately (via a reduced RF area), and more information is encoded by neurons (due to increased SNR).

Acute stress differently modulates interneurons excitability and synaptic plasticity in the primary motor cortex of wild-type and SOD1G93A mouse model of ALS.

Primary motor cortex (M1) network stability depends on activity of inhibitory interneurons, for which susceptibility to stress was previously demonstrated in limbic regions. Hyperexcitability in M1 following changes in the excitatory/inhibitory balance is a key pathological hallmark of amyotrophic lateral sclerosis (ALS). Using electrophysiological approaches, we assessed the impact of acute restraint stress on inhibitory interneurons excitability and global synaptic plasticity in M1 of the SOD1G93A ALS mouse model at a late pre-symptomatic stage (10-12.5weeks). Based on their firing type (continuous, discontinuous, with accommodation or not) and electrophysiological characteristics (resting potential, rheobase, firing frequency), interneurons from M1slices were separated into four clusters, labelled from 1 to 4. Among them, only interneurons from the first cluster, presenting continuous firing with few accommodations, tended to show increased excitability in wild-type (WT) and decreased excitability in SOD1G93A animals following stress. In vivo analyses of evoked field potentials showed that stress suppressed the theta burst-induced plasticity of an excitatory component (N1) recorded in the superficial layers of M1 in WT, with no impact on an inhibitory complex (N2-P1) from the deeper layers. In SOD1G93A mice, stress did not affect N1 but suppressed the N2-P1 plasticity. These data suggest that stress can alter M1 network functioning in a different manner in WT and SOD1G93A mice, possibly through changes of inhibitory interneurons excitability and synaptic plasticity. This suggests that stress-induced activity changes in M1may therefore influence ALS outcomes. KEY POINTS: Disruption of the excitatory/inhibitory balance in the primary motor cortex (M1) has been linked to cortical hyperexcitability development, a key pathological hallmark of amyotrophic lateral sclerosis (ALS). Psychological stress was reported to influence excitatory/inhibitory balance in limbic regions, but very little is known about its influence on the M1 functioning under physiological or pathological conditions. Our study revealed that acute stress influences the excitatory/inhibitory balance within the M1, through changes in interneurons excitability along with network plasticity. Such changes were different in pathological (SOD1G93A ALS mouse model) vs. physiological (wild-type) conditions. The results of our study help us to better understand how stress modulates the M1 and highlight the need to further characterize stress-induced motor cortex changes because it may be of importance when evaluating ALS outcomes.

Interneuron-selective HCN channel knockdown in prelimbic cortex of female rats mimics effects of chronic ethanol exposure

Our laboratory has previously shown that chronic ethanol exposure elicits enhanced working memory performance in female, but not male, adult Sprague–Dawley rats, indicative of a fundamental sex difference in cortical plasticity. Recent studies have furthermore revealed that females display markedly reduced HCN-mediated channel activity in inhibitory Martinotti interneurons after chronic ethanol exposure that is similarly not observed in males. From these observations we hypothesized that alcohol induces facilitated working memory performance via down-regulation of these channels’ activity specifically within interneurons. To test this hypothesis, we employed a Pol-II compatible shRNA expression system to elicit targeted knockdown of HCN channel activity in these cells, and measured performance on a delayed Non-Match-to-Sample (NMS) T-maze test to gauge effects on working memory performance. A significant baseline enhancement of working memory performance with HCN channel knockdown was observed, indicative of a critical role for interneuron-expressed HCNs in maintaining optimal cortical network activity during cognitively-demanding tasks. Consistent with previous observations, ethanol exposure resulted in enhanced NMS T-maze performance, however elevated working memory performance was observed in both scram- and hcn-shRNA infected groups after alcohol administration. We therefore conclude that interneuron-expressed HCN channels, despite representing a minor population of total cortical HCN expression, contribute substantially to maintaining working memory processes. Downregulated HCN channel activity, though, does not alone appear sufficient to manifest alcohol-induced enhancement of working memory performance observed in female rats during acute withdrawal.

A ventral pallidal-thalamocortical circuit mediates the cognitive control of instrumental action

Predictive learning can engage a selective form of cognitive control that biases choice between actions based on information about future outcomes that the learning provides. This influence has been hypothesized to depend on a feedback circuit in the brain through which the basal ganglia modulate activity in the prefrontal cortex; however, direct evidence for this functional circuit has proven elusive. Here, using an animal model of cognitive control, we found that the influence of predictive learning on decision making is mediated by an inhibitory feedback circuit linking the medial ventral pallidum and the mediodorsal thalamus, the activation of which causes disinhibition of the orbitofrontal cortex via reduced activation of inhibitory parvalbumin interneurons during choice. Thus, we found that, for this function, the mediodorsal thalamus serves as a pallidal-cortical relay through which predictive learning controls action selection, which has important implications for understanding cognitive control and its vicissitudes in various psychiatric disorders and addiction.

Abnormal local cortical functional connectivity due to interneuron dysmaturation after neonatal intermittent hypoxia.

Premature infants often experience frequent hypoxic episodes due to immaturity of respiratory control that may result in disturbances of gray and white matter development and long-term cognitive and behavioral abnormalities. We hypothesize that neonatal intermittent hypoxia alters cortical maturation of excitatory and inhibitory circuits that can be detected early with functional MRI. C57BL/6 mouse pups were exposed to an intermittent hypoxia (IH) regimen consisting of 12 to 20 daily hypoxic episodes of 5% oxygen exposure for 2 min at 37C from P3 to P7, followed by MRI at P12 and electrophysiological recordings in cortical slices and in vivo at several time points between P7 and P13. Behavioral tests were conducted at P41-P50 to assess animal activity and motor learning. Adult mice after neonatal IH exhibited hyperactivity in open field test and impaired motor learning in complex wheel tasks. Patch clamp and evoked field potential electrophysiology revealed increased glutamatergic transmission accompanied by elevation of tonic inhibition. A decreased synaptic inhibitory drive was evidenced by miniature IPSC frequency on pyramidal cells, multi-unit activity recording in vivo in the motor cortex with selective GABA A receptor inhibitor picrotoxin injection, as well as by the decreased interneuron density at P13. There was also an increased tonic depolarizing effect of picrotoxin after IH on principal cells' membrane potential on patch clamp and direct current potential in extracellular recordings. The amplitude of low-frequency fluctuation on resting-state fMRI was larger, with a larger increase after picrotoxin injection in the IH group. Increased excitatory glutamatergic transmission, decreased numbers, and activity of inhibitory interneurons after neonatal IH may affect the maturation of connectivity in cortical networks, resulting in long-term cognitive and behavioral changes, including impaired motor learning and hyperactivity. Functional MRI reveals increased intrinsic connectivity in the sensorimotor cortex, suggesting neuronal dysfunction in cortical maturation after neonatal IH. The increased tonic inhibition, presumably due to tonic extrasynaptic GABA receptor drive, may be compensatory to the elevated excitatory glutamatergic transmission.

Improved subjective sleep quality after three months of balance learning in older adults

Improved subjective sleep quality after three months of balance learning in older adults

Vasopressin differentially modulates the excitability of rat olfactory bulb neuron subtypes.

Vasopressin (VP) plays a crucial role in social memory even at the level of the olfactory bulb (OB), where OB VP cells are activated during social interactions. However, it remains unclear how VP modulates olfactory processing to enable enhanced discrimination of very similar odors, e.g., rat body odors. Thus far, it has been shown that VP reduces firing rates in mitral cells (MCs) during odor presentation in vivo and decreases the amplitudes of olfactory nerve-evoked excitatory postsynaptic potentials (ON-evoked EPSPs) in external tufted cells in vitro. We performed whole-cell patch-clamp recordings and population Ca2+ imaging on acute rat OB slices. We recorded ON-evoked EPSPs as well as spontaneous inhibitory postsynaptic currents (IPSCs) from two types of projection neurons: middle tufted cells (mTCs) and MCs. VP bath application reduced the amplitudes of ON-evoked EPSPs and the frequencies of spontaneous IPSCs in mTCs but did not change those in MCs. Therefore, we analyzed ON-evoked EPSPs in inhibitory interneurons, i.e., periglomerular cells (PGCs) and granule cells (GCs), to search for the origin of increased inhibition in mTCs. However, VP did not increase the amplitudes of evoked EPSPs in either type of interneurons. We next performed two-photon population Ca2+ imaging in the glomerular layer and the superficial GC layer of responses to stronger ON stimulation than during patch-clamp experiments that should evoke action potentials in the measured cells. We observed that VP application increased ON-evoked Ca2+ influx in juxtaglomerular cells and GC somata. Thus, our findings indicate inhibition by VP on projection neurons via strong ON input-mediated inhibitory interneuron activity. This neural modulation could improve representation of odors, hence, better discriminability of similar odors, e.g., conspecific body odors.

Optogenetic stimulation suppresses ictal activity in a 4-aminopyridine model of epileptic activity &lt;i&gt;in vitro&lt;/i&gt;

The WHO estimates that nearly 1% of the population suffers from epilepsy. Despite advances in the development of new antiepileptic drugs, seizures cannot be completely eliminated in nearly one-third of patients. One promising approach to the treatment of epilepsy may be gene therapy. Because epileptic activity is caused by an imbalance between excitation and inhibition, researchers have focused primarily on regulating neuronal excitability. Initially, the main approaches were based on the hyperexpression of inhibitory peptides such as galanin or NPY, or the suppression of neuronal excitability by the hyperexpression of potassium channels in neurons. However, these effects should be well calculated and strictly dosed, as it is difficult to correct the expression later. If the expression is too low, the anticonvulsant effect will not be achieved, and if the expression is too high, the neuronal networks will be impaired due to strong inhibition. For this reason, methodological approaches to treatment in which the effect on the neuronal excitability in the epileptic focus can be controlled are of great interest. Optogenetic methods offer such an advantage. Optogenetics uses light to alter the excitability of specific neuronal populations and can also be used in a biofeedback paradigm in which the light source is activated only at the risk of generating seizure activity. A number of optogenetic tools have now been developed, including light-activated cationic (e.g., ChR2) and anion channels (ACR), metabotropic receptors, pumps (NpHR, Arch), and enzymes. However, the optogenetic approach has a number of technical difficulties in delivering the light source and the risk of developing an immune response to the expression of rhodopsins. This report reviews the experience of practical application of optogenetic tools in the use of 4-aminopyridine in vitro model of epileptiform activity in experiencing slices of the entorhinal cortex. We tested the efficacy of suppressing ictal activity using several variants of optogenetic stimulation: (1) activation of excitatory and inhibitory neurons (in Thy1-ChR2-YFP mice), (2) activation of inhibitory interneurons only (in PV-Cre mice after virus injection with the channelodopsin-2 gene), hyperpolarization of excitatory neurons after expression of (3) archaeodopsin or (4) a light-dependent sodium pump. We found that ictal activity was successfully suppressed when low-frequency optogenetic stimulation induced regular interictal activity. Usually, interictal activity was induced by rhythmic synchronous activation of the principal neurons of the entorhinal cortex. In other cases, the ictal activity was preserved, although its characteristics may have changed. We determined the parameters of optogenetic stimulation that were most effective in suppressing ictal activity. The availability of a wide range of gene therapy approaches for epilepsy that have demonstrated efficacy in preclinical studies suggests that clinical trials of some of these approaches will begin in the next few years.

CA3 principal cell activation triggers hypersynchronous-onset seizures in a mouse model of mesial temporal lobe epilepsy.

Mesial temporal lobe epilepsy (MTLE) is the most common form of focal epilepsy and it is characterized by seizures that are often refractory to medications. Seizures in MTLE have two main patterns of onset that have been termed hypersynchronous (HYP) and low-voltage fast (LVF) and are believed to mainly depend on the activity of excitatory principal cells and inhibitory interneurons, respectively. In this study, we investigated whether unilateral open-loop optogenetic activation of CaMKII-positive principal cells in the hippocampus CA3 region favors the generation of spontaneous HYP seizures in kainic acid-treated (KA) CaMKII-ChR2 mice. Optogenetic activation of CA3 principal cells (1 Hz, 180 s ON, 220 s OFF) was implemented for 15 days after KA-induced status epilepticus. We found that both LVF and HYP seizures occurred in nonstimulated CaMKII-ChR2 (n = 6) and stimulated CaMKII-Cre (n = 5) mice. In contrast, optogenetic activation of principal cells in CaMKII-ChR2 mice (n = 5) triggered only HYP seizures that were characterized by high fast ripple (250-500 Hz) rates during the pre-ictal and ictal periods. These results provide firm evidence that in MTLE spontaneous seizures with different onset patterns depend on distinct neuronal network mechanisms of generation. They also demonstrate that HYP seizures occurring in vivo along with their associated fast ripples depend on the activity of principal cells in the CA3 region.NEW & NOTEWORTHY Previous evidence suggested that different seizure onset patterns rely on the activity of distinct neuronal populations. In this study, we show for the first time that in vivo optogenetic stimulation of CaMKII principal cells in kainic acid-treated mice triggers hypersynchronous-onset seizures that are associated with fast ripples. Our findings indicate that in patients with predominant HYP-onset seizures, anticonvulsant treatments should be aimed at limiting the firing of principal neurons in the seizure onset zone.

In vivo spontaneous activity and coital-evoked inhibition of mouse accessory olfactory bulb output neurons

Little is known about estrous effects on brain microcircuits. We examined the accessory olfactory bulb (AOB) invivo, in anesthetized naturally cycling females, as model microcircuit receiving coital somatosensory information. Whole-cell recordings demonstrate that output neurons are relatively hyperpolarized in estrus and unexpectedly fire high frequency bursts of action potentials. To mimic coitus, a calibrated artificial vagino-cervical stimulation (aVCS) protocol was devised. aVCS evoked stimulus-locked local field responses in the interneuron layer independent of estrous stage. The response is sensitive to α1-adrenergic receptor blockade, as expected since aVCS increases norepinephrine release in AOB. Intriguingly, only in estrus does aVCS inhibit AOB spike output. Estrus-specific output reduction coincides with prolonged aVCS activation of inhibitory interneurons. Accordingly, in estrus the AOB microcircuit sets the stage for coital stimulation to inhibit the output neurons, possibly via high frequency bursting-dependent enhancement of reciprocal synapse efficacy between inter- and output neurons.

Optogenetic manipulation of inhibitory interneurons can be used to validate a model of spatiotemporal sequence learning.

The brain uses temporal information to link discrete events into memory structures supporting recognition, prediction, and a wide variety of complex behaviors. It is still an open question how experience-dependent synaptic plasticity creates memories including temporal and ordinal information. Various models have been proposed to explain how this could work, but these are often difficult to validate in a living brain. A recent model developed to explain sequence learning in the visual cortex encodes intervals in recurrent excitatory synapses and uses a learned offset between excitation and inhibition to generate precisely timed "messenger" cells that signal the end of an instance of time. This mechanism suggests that the recall of stored temporal intervals should be particularly sensitive to the activity of inhibitory interneurons that can be easily targeted in vivo with standard optogenetic tools. In this work we examined how simulated optogenetic manipulations of inhibitory cells modifies temporal learning and recall based on these mechanisms. We show that disinhibition and excess inhibition during learning or testing cause characteristic errors in recalled timing that could be used to validate the model in vivo using either physiological or behavioral measurements.

Optogenetic activation of septal inhibitory cells abates focal seizures.

Emerging evidence suggests that the medial septum can control seizures occurring in focal epileptic disorders, thus representing a therapeutic target. Therefore, we investigated whether continuous optogenetic activation of inhibitory parvalbumin (PV)-positive interneurons in the medial septum can reduce the occurrence of spontaneous seizures in the pilocarpine model of mesial temporal lobe epilepsy (MTLE). Light pulses (450 nm, 25 mW, 20-ms pulse duration) were delivered at 0.5 Hz (5 min ON, 10 min OFF) with a laser diode fiber light source between day 8 and day 12 after status epilepticus (SE) in PV-ChR2 mice (n = 8). Seizure rates were significantly lower during time periods of optogenetic stimulation (days 8-12) compared with before implementation of optogenetics (days 4-7) (P < 0.05). Moreover, between day 13 and day 21 after SE seizure rates were still significantly lower compared with before optogenetic stimulation (i.e., between day 4 and day 7) (P < 0.05). No seizures were recorded between day 10 and day 12 in all animals, and no seizures occurred up to 3 days after the end of optogenetic stimulation (days 13-15). Our findings indicate that activation of PV interneurons in the medial septum abates seizures in the pilocarpine model of MTLE. Moreover, the persisting anti-ictogenic effects suggest that stimulation of the medial septum could alter the progression of MTLE.NEW & NOTEWORTHY The medial septum could represent a therapeutic target to treat patients with focal epilepsy. In this study, we show that optogenetic activation of inhibitory parvalbumin-positive interneurons in the medial septum can block spontaneous seizures and prevents their reoccurrence for ∼5 days after the end of stimulation. Our findings suggest that the anti-ictogenic effects induced by stimulation of the medial septum could also alter the progression of mesial temporal lobe epilepsy.

PV interneurons evoke astrocytic Ca2+ responses in awake mice, which contributes to neurovascular coupling.

Neurovascular coupling (NVC) modulates cerebral blood flow to match increased metabolic demand during neuronal excitation. Activation of inhibitory interneurons also increase blood flow, but the basis for NVC caused by interneurons is unclear. While astrocyte Ca2+ levels rise with excitatory neural transmission, much less is known with regards to astrocytic sensitivity to inhibitory neurotransmission. We performed two-photon microscopy in awake mice to examine the correlation between astrocytic Ca2+ and NVC, evoked by activation of either all (VGATIN ) or only parvalbumin-positive GABAergic interneurons (PVIN ). Optogenetic stimulation of VGATIN and PVIN in the somatosensory cortex triggered astrocytic Ca2+ increases that were abolished by anesthesia. In awake mice, PVIN evoked astrocytic Ca2+ responses with a short latency that preceded NVC, whereas VGATIN evoked Ca2+ increases that were delayed relative to the NVC response. The early onset of PVIN evoked astrocytic Ca2+ increases depended on noradrenaline release from locus coeruleus as did the subsequent NVC response. Though the relationship between interneuron activity and astrocytic Ca2+ responses is complex, we suggest that the rapid astrocyte Ca2+ responses to increased PVIN activity shaped the NVC. Our results underline that interneuron and astrocyte-dependent mechanisms should be studied in awake mice.

Multielectrode Cortical Stimulation Selectively Induces Unidirectional Wave Propagation of Excitatory Neuronal Activity in Biophysical Neural Model.

Cortical stimulation is emerging as an experimental tool in basic research and a promising therapy for a range of neuropsychiatric conditions. As multielectrode arrays enter clinical practice, the possibility of using spatiotemporal patterns of electrical stimulation to induce desired physiological patterns has become theoretically possible, but in practice can only be implemented by trial-and-error because of a lack of predictive models. Experimental evidence increasingly establishes traveling waves as fundamental to cortical information-processing, but we lack an understanding of how to control wave properties despite rapidly improving technologies. This study uses a hybrid biophysical-anatomical and neural-computational model to predict and understand how a simple pattern of cortical surface stimulation could induce directional traveling waves via asymmetric activation of inhibitory interneurons. We found that pyramidal cells and basket cells are highly activated by the anodal electrode and minimally activated by the cathodal electrodes, while Martinotti cells are moderately activated by both electrodes but exhibit a slight preference for cathodal stimulation. Network model simulations found that this asymmetrical activation results in a traveling wave in superficial excitatory cells that propagates unidirectionally away from the electrode array. Our study reveals how asymmetric electrical stimulation can easily facilitate traveling waves by relying on two distinct types of inhibitory interneuron activity to shape and sustain the spatiotemporal dynamics of endogenous local circuit mechanisms.SIGNIFICANCE STATEMENT Electrical brain stimulation is becoming increasingly useful to probe the workings of brain and to treat a variety of neuropsychiatric disorders. However, stimulation is currently performed in a trial-and-error fashion as there are no methods to predict how different electrode arrangements and stimulation paradigms will affect brain functioning. In this study, we demonstrate a hybrid modeling approach, which makes experimentally testable predictions that bridge the gap between the microscale effects of multielectrode stimulation and the resultant circuit dynamics at the mesoscale. Our results show how custom stimulation paradigms can induce predictable, persistent changes in brain activity, which has the potential to restore normal brain function and become a powerful therapy for neurological and psychiatric conditions.

Oligomeric β-Amyloid Suppresses Hippocampal γ-Oscillations through Activation of the mTOR/S6K1 Pathway.

Neuronal synchronization at gamma frequency (30-100 Hz: γ) is impaired in early-stage Alzheimer's disease (AD) patients and AD models. Oligomeric Aβ1-42 caused a concentration-dependent reduction of γ-oscillation strength and regularity while increasing its frequency. The mTOR1 inhibitor rapamycin prevented the Aβ1-42-induced suppression of γ-oscillations, whereas the mTOR activator leucine mimicked the Aβ1-42-induced suppression. Activation of the downstream kinase S6K1, but not inhibition of eIF4E, was required for the Aβ1-42-induced suppression. The involvement of the mTOR/S6K1 signaling in the Aβ1-42-induced suppression was confirmed in Aβ-overexpressing APP/PS1 mice, where inhibiting mTOR or S6K1 restored degraded γ-oscillations. To assess the network changes that may underlie the mTOR/S6K1 mediated γ-oscillation impairment in AD, we tested the effect of Aβ1-42 on IPSCs and EPSCs recorded in pyramidal neurons. Aβ1-42 reduced EPSC amplitude and frequency and IPSC frequency, which could be prevented by inhibiting mTOR or S6K1. These experiments indicate that in early AD, oligomer Aβ1-42 impairs γ-oscillations by reducing inhibitory interneuron activity by activating the mTOR/S6K1 signaling pathway, which may contribute to early cognitive decline and provides new therapeutic targets.

Optogenetic Low-Frequency Stimulation of Principal Neurons, but Not Parvalbumin-Positive Interneurons, Prevents Generation of Ictal Discharges in Rodent Entorhinal Cortex in an In Vitro 4-Aminopyridine Model

Low-frequency electrical stimulation is used to treat some drug-resistant forms of epilepsy. Despite the effectiveness of the method in suppressing seizures, there is a considerable risk of side effects. An optogenetic approach allows the targeting of specific populations of neurons, which can increase the effectiveness and safety of low-frequency stimulation. In our study, we tested the efficacy of the suppression of ictal activity in entorhinal cortex slices in a 4-aminopyridine model with three variants of low-frequency light stimulation (LFLS): (1) activation of excitatory and inhibitory neurons (on Thy1-ChR2-YFP mice), (2) activation of inhibitory interneurons only (on PV-Cre mice after virus injection with channelrhodopsin2 gene), and (3) hyperpolarization of excitatory neurons (on Wistar rats after virus injection with archaerhodopsin gene). Only in the first variant did simultaneous LFLS of excitatory and inhibitory neurons replace ictal activity with interictal activity. We suggest that LFLS caused changes in the concentration gradients of K+ and Na+ cations across the neuron membrane, which activated Na-K pumping. According to the mathematical modeling, the increase in Na-K pump activity in neurons induced by LFLS led to an antiepileptic effect. Thus, a less specific and generalized optogenetic effect on entorhinal cortex neurons was more effective in suppressing ictal activity in the 4-aminopyridine model.

Expression of a Form of Cerebellar Motor Memory Requires Learned Alterations to the Activity of Inhibitory Molecular Layer Interneurons.

Procedural memories formed in the cerebellum in response to motor errors depend on changes to Purkinje cell (PC) spiking patterns that correct movement when the erroneous context is repeated. Because molecular layer interneurons (MLIs) inhibit PCs, learning-induced changes to MLI output may participate in reshaping PC spiking patterns. However, it remains unclear whether error-driven learning alters MLI activity and whether such changes are necessary for the memory engram. We addressed this knowledge gap by measuring and manipulating MLI activity in the flocculus of both sexes of mice before and after vestibulo-ocular reflex (VOR) adaptation. We found that MLIs are activated during vestibular stimuli and that their population response exhibits a phase shift after the instantiation of gain-increase VOR adaptation, a type of error-driven learning thought to require climbing-fiber-mediated instructive signaling. Although acute optogenetic suppression of MLI activity did not affect baseline VOR performance, it negated the expression of gain-increase learning, demonstrating a specific role of MLI activity changes in motor memory expression. This effect was transitory; after a multiday consolidation period, the expression of VOR gain-increase learning was no longer sensitive to MLI activity suppression. Together, our results indicate that error-driven alteration of MLI activity is necessary for labile, climbing-fiber-induced motor memory expression.SIGNIFICANCE STATEMENT In the cerebellum, motor learning induces an associative memory of the sensorimotor context of an erroneous movement that, when recalled, results in a new pattern of output that improves subsequent trials of performance. Our study shows that error-driven motor learning induces changes to the activity pattern of cerebellar molecular layer interneurons (MLIs) and that this new pattern of activity is required to express the corrective motor memory.

Chronic hM3Dq-DREADD-mediated chemogenetic activation of parvalbumin-positive inhibitory interneurons in postnatal life alters anxiety and despair-like behavior in adulthood in a task- and sex-dependent manner

Animal models of early adversity or neurodevelopmental disorders are associated with altered parvalbumin (PV)-positive inhibitory interneuron number and function, correlated with a dysregulated excitation-inhibition (E/I) balance that is implicated in the pathophysiology of neuropsychiatric disorders. We sought to address whether altering neuronal activity of PV-positive interneurons during the postnatal developmental window influences the emergence of anxio-depressive behaviors in adulthood, which are known to be perturbed in models of early adversity and neurodevelopmental disorders. We used a PV-Cre::hM3Dq-DREADD bigenic mouse line that selectively expresses the hM3Dq-DREADD receptor in PV-positive interneurons, and chemogenetically enhanced Gq signaling in PV-positive interneurons during the postnatal window via administration of the DREADD agonist, clozapine-N-oxide. Immunofluorescence studies have indicated the selective expression of hM3Dq-DREADD in PV-positive interneurons in limbic circuits, and have revealed a reduction in expression of the neuronal activity marker, c-Fos, in these circuits, following chemogenetic hM3Dq-DREADD-mediated activation of PV-positive inhibitory interneurons. We noted no change in either growth or sensorimotor reflex milestones following chronic hM3Dq-DREADD-mediated chemogenetic activation of PV-positive inhibitory interneurons in postnatal life. Adult male and female PV-Cre::hM3DqDREADD bigenic mice with a history of postnatal chemogenetic activation of PV-positive interneurons exhibited a reduction in anxiety and despair-like behavior in adulthood, which was noted in both a behavioral task- and sex-dependent manner. These results indicate that altering neuronal activity within PV-positive interneurons during the critical postnatal developmental window can shape the emergence of anxio-depressive behaviors in adulthood, with sex as a variable playing a key role in determining behavioral outcomes.

Anxiety-related activity of ventral hippocampal interneurons.

Anxiety is an aversive mood reflecting the anticipation of potential threats. The ventral hippocampus (vH) is a key brain region involved in the genesis of anxiety responses. Recent studies have shown that anxiety is mediated by the activation of vH pyramidal neurons targeting various limbic structures. Throughout the cortex, the activity of pyramidal neurons is controlled by GABA-releasing inhibitory interneurons and the GABAergic system represents an important target of anxiolytic drugs. However, how the activity of vH inhibitory interneurons is related to different anxiety behaviours has not been investigated so far. Here, we integrated in vivo electrophysiology with behavioural phenotyping of distinct anxiety exploration behaviours in rats. We showed that pyramidal neurons and interneurons of the vH are selectively active when animals explore specific compartments of the elevated-plus-maze (EPM), an anxiety task for rodents. Moreover, rats with prior goal-related experience exhibited low-anxiety exploratory behaviour and showed a larger trajectory-related activity of vH interneurons during EPM exploration compared to high anxiety rats. Finally, in low anxiety rats, trajectory-related vH interneurons exhibited opposite activity to pyramidal neurons specifically in the open arms (i.e. more anxiogenic) of the EPM. Our results suggest that vH inhibitory micro-circuits could act as critical elements underlying different anxiety states.