Recent work in rodent models provides mechanistic insights into how the excitability of principal neurons is dynamically regulated to facilitate the encoding and retrieval of emotionally salient memories in the basolateral amygdala (BLA). In this review, we discuss the physiological mechanisms governing BLA excitability, emphasizing their impact on the recruitment of defined BLA ensembles encoding distinct behavioral states. In addition, we summarize the current understanding of how these mechanisms are established during development and suggest that this may follow distinct developmental phases. Lastly, we outline recent findings on how early-life adversity or genetic risk factors can acutely perturb developmental trajectories and may lead to enduring changes in BLA circuit function, with implications for neurodevelopmental disorders.

The prefrontal cortex orchestrates complex behaviors by communicating with subcortical structures through synchronized oscillations. Here we show that ablation of GluK1 subunit-containing kainate receptors in parvalbumin interneurons (PV INs) disrupts oscillatory dynamics in the cortico-hippocampal circuits mediating social and cognitive behaviors. In control mice, the hippocampus-medial prefrontal cortex (HC-mPFC) circuit displayed elevated theta and gamma oscillation power as well as enhanced functional coupling during interaction with a familiar mouse. Similar circuit dynamics were not observed during interaction with a novel mouse, consistent with the idea that social recognition involves cortico-hippocampal communication. Mice lacking GluK1 in the PV INs (PV-Grik1-/-) showed defects in cognitive flexibility and social discrimination as well as impaired neurochemical phenotype of PV INs in the HC and mPFC. Electrophysiological recordings in the PV-Grik1-/- mice revealed elevated theta and gamma oscillation power in both HC and mPFC along with enhanced functional coupling between these brain regions at rest. In contrast to the controls, no changes in the theta and gamma oscillation powers in the HC or mPFC or in the HC-mPFC coupling were detected in the PV-Grik1-/- mice during social interaction. Our data suggest that impaired functional dynamics in cortico-hippocampal circuits in the PV-Grik1-/- mice compromise social discrimination and shed light on the neurobiological mechanisms by which GluK1 dysfunction may contribute to neuropsychiatric disorders.

The MECP2 gene is located on the X chromosome and encodes a methyl-CpG-binding protein 2 involved in transcriptional regulation. Loss-of-function mutations in the MECP2 gene lead to Rett syndrome, a severe neurodevelopmental disorder. The clinical picture of Rett syndrome includes, among other symptoms, social deficits, learning impairment, and heightened anxiety. The amygdala is a brain region responsible for emotional learning and is involved in the regulation of social behaviour as well as fear and anxiety. Parvalbumin interneurons tightly control the excitability, oscillation and synchronisation of the amygdala network, which are relevant to its functions. Here, we investigated the effects of Mecp2 gene ablation in parvalbumin interneurons on the microcircuit and functional connectivity of the mouse amygdala. Male mice with conditional knockout of the Mecp2 gene in parvalbumin interneurons were used as a genetic mouse model. Littermates with an intact gene were used as controls. Ex vivo brain slice electrophysiology, combined with pharmacology and optogenetics, was utilised to characterise microcircuits within the lateral amygdala. In vivo functional ultrasound imaging was used to visualise the connectivity within the amygdala–ventral hippocampus–prefrontal cortex network triad. Loss of Mecp2 in parvalbumin interneurons significantly attenuated GABAergic synaptic input to principal neurons in the lateral amygdala. The deficit in inhibition was accompanied by higher excitability of local principal neurons in adult animals. A deficient in vivo functional connectivity of the amygdala with the ventral hippocampus and prefrontal cortex was observed in conditional knockouts. This study used only male mice. Mecp2 knockout males exhibit shorter latency to symptom onset and lower phenotypic variability, making them suitable for mechanistic studies. Since previous studies in the field used males, we aimed to advance the existing body of research using the same approach. Finally, the link between the effects observed and possible behavioural alterations needs further investigation. Our study characterised the consequences of Mecp2 loss in parvalbumin interneurons on amygdala microcircuit function and connectivity within the prefrontal cortex‒amygdala‒hippocampus triad. It also provided evidence that supports and complements previous findings on the role of interneurons in the functional deficits observed in Mecp2 knockout animal models.

m6A methylation is the most abundant modification in eukaryotic mRNA and has been implicated in epitranscriptomic regulation of various cellular functions. Recent studies have demonstrated its significance in brain development, neuronal signalling and memory formation; however, the precise mechanisms by which m6A RNA methylation affects synaptic transmission and plasticity in memory-related neuronal circuits remain unclear. Here, we have studied the effects of newly developed pharmacological compounds that target m6A methylation on excitatory synaptic transmission and plasticity in the hippocampus, using a combination of electrophysiological and immunohistological techniques in infant and adult rats. We demonstrate that STM2457, a highly potent catalytic inhibitor of the m6A methyltransferase METTL3, blocks long-term potentiation (LTP) without affecting basal synaptic transmission in area CA1. Moreover, our findings support that LTP in vivo is associated with elevated m6A immunostaining, suggesting that LTP induction triggers METTL3 activation and a subsequent rise in m6A methylation. Interestingly, pharmacological activation of METTL3/14 or inhibition of the m6A demethylase FTO increased synaptic m6A levels in vivo, yet attenuated LTP in adult hippocampal slices. METTL3/14 activation also diminished long-term depression (LTD). These findings align with a model where elevated m6A methylation acts as a stabilizing signal, limiting excessive activity-dependent plasticity of synaptic transmission across development. Furthermore, they add to the growing body of evidence supporting that dysregulation of m6A RNA methylation perturbs synaptic plasticity - the neurobiological foundation of memory - and demonstrate that these processes can be pharmacologically targeted.

Genetic variants affecting brain development can lead to an increased risk of neurological disorders later in life. A protein-truncating variant in a gene for secreted neural protein LGI2 (Leucine-rich glioma-inactivated 2) is associated with remitting focal juvenile epilepsy and later behavioural disorders in Lagotto Romagnolo dogs. Yet, the developmental expression pattern of LGI2 in the brain and its association with neuronal network activities and behaviour have not been characterized. Here we show that Lgi2 gene expression is low in the neonatal mouse hippocampus but increases during juvenility (P14). Lgi2 is mainly expressed in GABAergic interneurons. Electrophysiological recordings using hippocampal slice cultures from LGI2 deficient mice revealed that Lgi2 ablation provokes ictal-like activity. We also found that adult LGI2-deficient mice have deficits in spatial reversal learning and impaired cognitive flexibility, thus paralleling Lagottos' behavioural ailments with ADHD-like symptoms. Therefore, our mouse model reveals functional defects in developing LGI2 deficient networks that associate with neurological disorders manifesting later in life.

The developmental shift from depolarizing to hyperpolarizing GABA responses is a pivotal step in the maturation of GABAergic transmission and cortical circuits; classically documented in principal neurons during the first postnatal week in the mouse cortex. Surprisingly, whether maturation of GABA-mediated responses follows the same temporal pattern in cortical interneurons (INs) remains unresolved. Leveraging an array of methods, a high-resolution cortical development mouse atlas and single-cell RNA sequencing, we identify and comprehensively characterize a population of early-maturing cortical INs in mice, distinguished by KCC2 expression at embryonic stages and concomitant hyperpolarizing GABAA responses at birth. These early KCC2-expressing INs exhibit precocious intrinsic excitability, synaptic integration, and dendritic complexity at birth, contrasting delayed maturation in principal neurons and other INs. Spatial transcriptomics and differential gene expression (DGE) analyses reveal early KCC2-expressing INs localize predominantly to layer 5, express somatostatin, and show upregulation of synaptogenic genes, consistent with the recorded elevated synaptic activity. Crucially, evolutionary conservation of early KCC2-expressing INs in humans was demonstrated with analogous genetic profiles enriched for signaling and synaptic maturation pathways. This work resolves a critical gap in developmental neurobiology, demonstrating heterogenous GABAergic functional maturation within IN subpopulations and establishing KCC2 as a marker of early-maturing INs. Authors report early-maturing cortical interneurons express KCC2 embryonically, show hyperpolarizing GABA responses, advanced morpho-physiology, synaptic integration, and gene expression. This conserved feature highlights KCC2 as a key marker of interneuron development.

Early-life stress (ELS) induces persistent amygdala dysfunction and affects amygdala-related emotional behaviors, yet the developmental and physiological mechanisms driving these effects remain poorly understood. Here, we provide a comprehensive electrophysiological characterization of the effects of ELS on parvalbumin and somatostatin interneurons (INs) as well as principal neurons (PNs) in the mouse lateral amygdala (LA) across development. Additionally, we correlate these findings to activity of the LA circuitry in vivo , using Neuropixels recordings in awake mice. In preweaning juveniles, the effects of ELS were remarkably similar in males and females, involving reduced IN excitability, elevated glutamatergic input to INs and shift in the PN E/I balance. While IN function was largely normalized in adult females, males developed a distinct pathological phenotype characterized by reduced glutamatergic input to INs, impaired recruitment of INs and hyperexcitability of PNs. This male-specific dysfunction correlated with aberrant LA oscillatory dynamics in awake mice and deficits in fear processing. Our data suggest that the impaired glutamatergic wiring of interneurons is a key mechanism underlying the aberrant circuit dynamics in the LA after ELS exposure and contribute to the ELS-induced defects in fear processing. These findings highlight sex-specific developmental trajectories of interneuron connectivity as a potential factor contributing to ELS-induced psychiatric vulnerability. ### Competing Interest Statement The authors have declared no competing interest. Research Council of Finland, https://ror.org/05k73zm37 Sigrid Jusélius Foundation, https://ror.org/00ckakm23 Jane and Aatos Erkko Foundation, https://ror.org/03vxy9y38 Finnish Cultural Foundation, https://ror.org/027xav248 Orion Research Foundation

Organotypic hippocampal slices (OHSs) grown on multielectrode arrays (MEAs) provide unique means to investigate network activity in the same slice over a long period. However, hippocampal activity may not be consistent across different culture media. In this study, we compared two standard culture media with the novel BrainPhys medium to investigate the effect of medium on OHS gross morphological structure and network activity. First, we compared OHS surface area in three different culture media: serum-containing Dulbecco's Modified Eagle Medium (DMEM)-based medium, serum-free Neurobasal-A (NB-A), and serum-free BrainPhys. Our results show that the surface area of the hippocampal slice was well preserved in serum-free culture media, but not in serum-based DMEM. Second, we studied spontaneous network activity in OHS at 7 days in vitro in NB-A and BrainPhys media. In BrainPhys medium, fewer OHS had spontaneous epileptiform activity than in NB-A. Third, we induced epileptic-like activity with 2 µM kainic acid (KA) in OHS cultured either in NB-A or BrainPhys. After 6 h of KA treatment and 24 h recovery period, cultures grown in BrainPhys developed spontaneous epileptiform activity, while activity of OHSs in NB-A did not differ from the activity before KA treatment. We conclude that when cultured on MEA, OHS retain their gross morphological structure better in serum-free culture media than in serum-containing DMEM. Furthermore, BrainPhys supports the physiological network activity of OHSs during the first week in culture and is well suited medium for studies of epileptogenesis in vitro.

Amygdala hyperexcitability is a hallmark of stress-induced anxiety disorders. Stress-associated changes in both principal neurons and interneurons contribute to the increased excitability, but how exactly these mechanisms interact to regulate the function of behaviorally relevant circuits in the amygdala remains unclear. Here, we show that GluK1 subunit-containing kainate receptors in parvalbumin (PV) interneurons maintain high GABA release and control excitability of lateral amygdala (LA) principal neurons via tonic GABAB-receptor-mediated inhibition. Downregulation of GluK1 expression in PV interneurons after chronic restraint stress (CRS) releases the tonic inhibition and increases excitability of LA principal neurons. Stress-induced LA hyperexcitability was associated with increased glutamatergic transmission to central amygdala PKCδ-expressing neurons, implicated in fear generalization. Consistent with significance in anxiogenesis, absence of GluK1-GABAB regulation confers resilience against CRS-induced LA hyperexcitability and anxiety-like behavior. Our data reveal a unique novel mechanism involving an interplay between glutamatergic and GABAergic systems in the regulation of amygdala excitability in response to chronic stress.

Birth stress is a risk factor for psychiatric disorders and associated with exaggerated release of the stress hormone arginine vasopressin (AVP) into circulation and in the brain. In perinatal hippocampus, AVP activates GABAergic interneurons which leads to suppression of spontaneous network events and suggests a protective function of AVP on cortical networks during birth. However, the role of AVP in developing subcortical networks is not known. Here we tested the effect of AVP on the dorsal raphe nucleus (DRN) 5-hydroxytryptamine (5-HT, serotonin) system in male and female neonatal rats, since early 5-HT homeostasis is critical for the development of cortical brain regions and emotional behaviors. We show that AVP is strongly excitatory in neonatal DRN: it increases excitatory synaptic inputs of 5-HT neurons via V1A receptors in vitro and promotes their action potential firing through a combination of its effect on glutamatergic synaptic transmission and a direct effect on the excitability of these neurons. Furthermore, we identified two major firing patterns of neonatal 5-HT neurons in vivo, tonic regular firing and low frequency oscillations of regular spike trains and confirmed that these neurons are also activated by AVP in vivo. Finally, we show that the sparse vasopressinergic innervation in neonatal DRN originates exclusively from cell groups in medial amygdala and bed nucleus of stria terminalis. Hyperactivation of the neonatal 5-HT system by AVP during birth stress may impact its own functional development and affect the maturation of cortical target regions, which may increase the risk for psychiatric conditions later on.

Amygdala hyperexcitability is a hallmark for stress-induced anxiety disorders. Stress-associated changes in both principal neurons and interneurons contribute to the increased excitability, but how exactly these mechanisms perturb function of behaviorally relevant circuits in the amygdala remains unclear. Here, we show that GluK1 subunit-containing kainate receptors in parvalbumin (PV) interneurons maintain high GABA release and control excitability of lateral amygdala (LA) principal neurons via tonic GABAB-receptor-mediated inhibition. Downregulation of GluK1 expression in PV interneurons after chronic restraint stress (CRS) releases the tonic inhibition and increases excitability of LA principal neurons. Stress-induced LA hyperexcitability facilitates glutamatergic transmission selectively to central amygdala PKCδ-expressing neurons, implicated in fear generalization. Consistent with significance in anxiogenesis, absence of GluK1- GABAB regulation confers resilience against CRS-induced LA hyperexcitability and anxiety-like behavior. Our data reveal a unique novel mechanism involving an interplay between glutamatergic and GABAergic systems in the regulation of amygdala excitability in response to chronic stress.### Competing Interest StatementThe authors have declared no competing interest.

Parvalbumin expressing interneurons (PV INs) are key players in the local inhibitory circuits and their developmental maturation coincides with the onset of adult-type network dynamics in the brain. Glutamatergic signaling regulates emergence of the unique PV IN phenotype, yet the receptor mechanisms involved are not fully understood. Here we show that GluK1 subunit containing kainate receptors (KARs) are necessary for development and maintenance of the neurochemical and functional properties of PV INs in the lateral and basal amygdala (BLA). Ablation of GluK1 expression specifically from PV INs resulted in low parvalbumin expression and loss of characteristic high firing rate throughout development. In addition, we observed reduced spontaneous excitatory synaptic activity at adult GluK1 lacking PV INs. Intriguingly, inactivation of GluK1 expression in adult PV INs was sufficient to abolish their high firing rate and to reduce PV expression levels, suggesting a role for GluK1 in dynamic regulation of PV IN maturation state. The PV IN dysfunction in the absence of GluK1 perturbed the balance between evoked excitatory vs. inhibitory synaptic inputs and long-term potentiation (LTP) in LA principal neurons, and resulted in aberrant development of the resting-state functional connectivity between mPFC and BLA. Behaviorally, the absence of GluK1 from PV INs associated with hyperactivity and increased fear of novelty. These results indicate a critical role for GluK1 KARs in regulation of PV IN function across development and suggest GluK1 as a potential therapeutic target for pathologies involving PV IN malfunction.

Kainate type glutamate receptors (KARs) are strongly expressed in GABAergic interneurons and have the capability of modulating their functions via ionotropic and G-protein coupled mechanisms. GABAergic interneurons are critical for generation of coordinated network activity in both neonatal and adult brain, yet the role of interneuronal KARs in network synchronization remains unclear. Here, we show that GABAergic neurotransmission and spontaneous network activity is perturbed in the hippocampus of neonatal mice lacking GluK1 KARs selectively in GABAergic neurons. Endogenous activity of interneuronal GluK1 KARs maintains the frequency and duration of spontaneous neonatal network bursts and restrains their propagation through the hippocampal network. In adult male mice, the absence of GluK1 in GABAergic neurons led to stronger hippocampal gamma oscillations and enhanced theta-gamma cross frequency coupling, coinciding with faster spatial relearning in the Barnes maze. In females, loss of interneuronal GluK1 resulted in shorter sharp wave ripple oscillations and slightly impaired abilities in flexible sequencing task. In addition, ablation of interneuronal GluK1 resulted in lower general activity and novel object avoidance, while causing only minor anxiety phenotype. These data indicate a critical role for GluK1 containing KARs in GABAergic interneurons in regulation of physiological network dynamics in the hippocampus at different stages of development.

Kainate receptors are potent modulators of circuit excitability and have been repeatedly implicated in pathophysiological synchronization of limbic networks. While the role of aberrant GluK2 subunit containing KARs in generation of epileptiform hypersynchronous activity is well described, the contribution of other KAR subtypes, including GluK1 subunit containing KARs remain less well understood. To investigate the contribution of GluK1 KARs in developmental and pathological synchronization of the hippocampal neural network, we used multielectrode array recordings on organotypic hippocampal slices that display first multi-unit activity and later spontaneous population discharges resembling ictal-like epileptiform activity (IEA). Chronic blockage of GluK1 activity using selective antagonist ACET or lentivirally delivered shRNA significantly delayed developmental synchronization of the hippocampal CA3 network and generation of IEA. GluK1 overexpression, on the other hand, had no significant effect on occurrence of IEA, but enhanced the size of the neuron population participating in the population discharges. Correlation analysis indicated that local knockdown of GluK1 locally in the CA3 neurons reduced their functional connectivity, while GluK1 overexpression increased the connectivity to both CA1 and DG. These data suggest that GluK1 KARs regulate functional connectivity between the excitatory neurons, possibly via morphological changes in glutamatergic circuit, affecting synchronization of neuronal populations. The significant effects of GluK1 manipulations on network activity call for further research on GluK1 KAR as potential targets for antiepileptic treatments, particularly during the early postnatal development when GluK1 KARs are strongly expressed in the limbic neural networks.

Critical period-like plasticity (iPlasticity) can be reinstated in the adult brain by several interventions, including drugs and optogenetic modifications. We have demonstrated that a combination of iPlasticity with optimal training improves behaviors related to neuropsychiatric disorders. In this context, the activation of TrkB, a receptor for BDNF, in Parvalbumin-positive (PV + ) interneurons has a pivotal role in cortical network changes. However, it is unknown if the activation of TrkB in PV + interneurons is important for other plasticity-related behaviors, especially for learning and memory. Here, using mice with heterozygous conditional TrkB deletion in PV + interneurons (PV-TrkB hCKO) in IntelliCage and fear erasure paradigms, we show that chronic treatment with fluoxetine, a widely prescribed antidepressant drug that is known to promote the activation of TrkB, enhances behavioral flexibility in spatial and fear memory, largely depending on the expression of the TrkB receptor in PV + interneurons. In addition, hippocampal long-term potentiation was enhanced by chronic treatment with fluoxetine in wild-type mice, but not in PV-TrkB hCKO mice. Transcriptomic analysis of PV + interneurons after fluoxetine treatment indicated intrinsic changes in synaptic formation and downregulation of enzymes involved in perineuronal net formation. Consistently, immunohistochemistry has shown that the fluoxetine treatment alters PV expression and reduces PNNs in PV + interneurons, and here we show that TrkB expression in PV + interneurons is required for these effects. Together, our results provide molecular and network mechanisms for the induction of critical period-like plasticity in adulthood.

Early life stress (ELS) results in enduring dysfunction of the cortico-limbic circuitry, underlying emotional and social behavior. However, the neurobiological mechanisms by which ELS affects development of the circuitry remain elusive. Here, we have combined viral tracing and electrophysiological techniques to study the effects of maternal separation (MS) on fronto-limbic connectivity and function in young (P14-21) rats. We report that aberrant prefrontal (mPFC) inputs to basolateral amygdala (BLA) GABAergic interneurons transiently increase the strength of feedforward inhibition in the BLA, which raises LTP induction threshold in MS treated male rats. The enhanced GABAergic activity after MS exposure associates with lower functional synchronization within prefrontal-amygdala networks in vivo. Intriguingly, no differences in these parameters were detected in females, which were also resistant to MS dependent changes in anxiety-like behaviors. Impaired plasticity and synchronization during the sensitive period of circuit refinement may contribute to long-lasting functional changes in the prefrontal-amygdaloid circuitry that predispose to neuropsychiatric conditions later on in life.

It is unclear how binding of antidepressant drugs to their targets gives rise to the clinical antidepressant effect. We discovered that the transmembrane domain of tyrosine kinase receptor 2 (TRKB), the brain-derived neurotrophic factor (BDNF) receptor that promotes neuronal plasticity and antidepressant responses, has a cholesterol-sensing function that mediates synaptic effects of cholesterol. We then found that both typical and fast-acting antidepressants directly bind to TRKB, thereby facilitating synaptic localization of TRKB and its activation by BDNF. Extensive computational approaches including atomistic molecular dynamics simulations revealed a binding site at the transmembrane region of TRKB dimers. Mutation of the TRKB antidepressant-binding motif impaired cellular, behavioral, and plasticity-promoting responses to antidepressants in vitro and in vivo. We suggest that binding to TRKB and allosteric facilitation of BDNF signaling is the common mechanism for antidepressant action, which may explain why typical antidepressants act slowly and how molecular effects of antidepressants are translated into clinical mood recovery.

Kainate receptors (KARs) are highly expressed in the immature brain and have unique developmentally regulated functions that may be important in linking neuronal activity to morphogenesis during activity-dependent fine-tuning of the synaptic connectivity. Altered expression of KARs in the developing neural network leads to changes in glutamatergic connectivity and network excitability, which may lead to long-lasting changes in behaviorally relevant circuitries in the brain. Here, we summarize the current knowledge on physiological and morphogenic functions described for different types of KARs at immature neural circuitries, focusing on their roles in modulating synaptic transmission and plasticity as well as circuit maturation in the rodent hippocampus and amygdala. Finally, we discuss the emerging evidence suggesting that malfunction of KARs in the immature brain may contribute to the pathophysiology underlying developmentally originating neurological disorders.

Early life stress (ELS) is a well-characterized risk factor for mood and anxiety disorders. GABAergic microcircuits in the amygdala are critically implicated in anxiety; however, whether their function is altered after ELS is not known. Here we identify a novel mechanism by which kainate receptors (KARs) modulate feedforward inhibition in the lateral amygdala (LA) and show that this mechanism is downregulated after ELS induced by maternal separation (MS). Specifically, we show that in control rats but not after MS, endogenous activity of GluK1 subunit containing KARs disinhibit LA principal neurons during activation of cortical afferents. GluK1 antagonism attenuated excitability of parvalbumin (PV)-expressing interneurons, resulting in loss of PV-dependent inhibitory control and an increase in firing of somatostatin-expressing interneurons. Inactivation of Grik1 expression locally in the adult amygdala reduced ongoing GABAergic transmission and was sufficient to produce a mild anxiety-like behavioral phenotype. Interestingly, MS and GluK1-dependent phenotypes showed similar gender specificity, being detectable in male but not female rodents. Our data identify a novel KAR-dependent mechanism for cell-type and projection-specific functional modulation of the LA GABAergic microcircuit and suggest that the loss of GluK1 KAR function contributes to anxiogenesis after ELS.

Successful extinction of traumatic memories depends on neuronal plasticity in the fear extinction network. However, the mechanisms involved in the extinction process remain poorly understood. Here, we investigated the fear extinction network by using a new optogenetic technique that allows temporal and spatial control of neuronal plasticity in vivo. We optimized an optically inducible TrkB (CKII-optoTrkB), the receptor of the brain-derived neurotrophic factor, which can be activated upon blue light exposure to increase plasticity specifically in pyramidal neurons. The activation of CKII-optoTrkB facilitated the induction of LTP in Schaffer collateral-CA1 synapses after brief theta-burst stimulation and increased the expression of FosB in the pyramidal neurons of the ventral hippocampus, indicating enhanced plasticity in that brain area. We showed that optical stimulation of the CA1 region of the ventral hippocampus during fear extinction training led to an attenuated conditioned fear memory. This was a specific effect only observed when combining extinction training with CKII-optoTrkB activation, and not when using either intervention alone. Thus, TrkB activation in ventral CA1 pyramidal neurons promotes a state of neuronal plasticity that allows extinction training to guide neuronal network remodeling to overcome fear memories. Our methodology is a powerful tool to induce neuronal network remodeling in the adult brain, and can attenuate neuropsychiatric symptoms caused by malfunctioning networks.