Biology subjects

Lauri, S. E.

Publications and source records attributed to Lauri, S. E..

7 recordsLinked to original sources

bioRxiv2024

Loss of the MeCP2 gene in parvalbumin interneurons leads to an inhibitory deficit in the amygdala and affects its functional connectivity.

BackgroundMECP2 gene is located in the X-chromosome and encodes a methyl-CpG-binding protein involved in transcription regulation. The loss-of-function mutation of the MECP2 gene, leads to severe neurodevelopmental syndrome, Rett syndrome. Clinical picture of Rett syndrome includes, among other symptoms, social deficits and heightened anxiety. The amygdala is involved in the regulation of social behavior as well as fear and anxiety. Here, we investigated the effect of the MeCP2 gene ablation in the parvalbumin interneurons on the microcircuit and functional connectivity of the amygdala. MethodsMales with conditional knock-out of the MeCP2 gene in the parvalbumin interneurons were used as a genetic mouse model of MeCP2 loss in parvalbumin interneurons. Littermates with the intact gene were used as controls. Ex-vivo brain slice electrophysiology, combined with pharmacology and optogenetics, was used to characterize microcircuits within the lateral amygdala. Synaptic currents and excitability of parvalbumin interneurons and principal neurons were analyzed by a whole-cell patch clamp. In-vivo functional ultrasound was used to visualize the connectivity within the amygdala-ventral hippocampus-prefrontal cortex triad. ResultsLoss of MeCP2 in parvalbumin interneurons significantly reduced the GABAergic synaptic input to the principal neurons in the lateral amygdala. The decreased inhibitory drive was accompanied by an increase in the excitability of principal neurons in the lateral amygdala. The in vivo functional connectivity of the amygdala-ventral hippocampus and amygdala-prefrontal cortex was significantly reduced in conditional knock-outs compared to their littermates with the intact gene in the X chromosome. ConclusionsOur study characterized the consequences of MeCP2 gene loss in the parvalbumin interneurons on the amygdala connectivity and microcircuit and provided evidence supporting the previous findings on the role of interneurons in the functional deficit observed in animal models with MeCP2 loss.

neuroscience↗

bioRxiv2024

Arginine vasopressin activates serotonergic neurons in the dorsal raphe nucleus during neonatal development in vitro and in vivo

Birth stress is a strong risk factor for psychiatric disorders and associated with an exaggerated release of the stress hormone arginine vasopressin (AVP) into circulation and in the brain. While it has been shown that AVP promotes firing of GABAergic interneurons leading to suppression of spontaneous perinatal hippocampal network events that suggest a protective function, its effect on developing subcortical networks is not known. Here we tested the effect of AVP on the neonatal dorsal raphe nucleus (DRN) 5-hydroxytryptamine (5-HT, serotonin) system, since early 5-HT homeostasis is critical for the development of cortical brain regions and emotional behaviors. Using in vitro electrophysiological recording techniques, we show that AVP strongly excites neonatal 5-HT neurons via V1A receptors by increasing their excitatory synaptic inputs. Accordingly, AVP also promotes action potential firing through a combination of its effect on glutamatergic synaptic transmission and a direct effect on the excitability of 5-HT neurons. Our in vivo single unit recordings of identified neonatal 5-HT neurons under light urethane anaesthesia revealed two major firing patterns of neonatal 5-HT neurons, tonic regular firing and low frequency oscillations of regular spike trains. We confirmed that AVP also increases firing activity of putative 5-HT neurons in neonatal DRN in vivo. Finally, we show that neonatal DRN contains a sparse vasopressinergic innervation that is strongly sex dependent and originates exclusively from vasopressinergic cell groups in medial amygdala and bed nucleus of stria terminalis (BNST). Our results show, that in contrast to developing cortical networks where AVP promotes inhibition, AVP can also be strongly excitatory in immature subcortical networks such as the DRN 5-HT system. Hyperactivation of the neonatal 5-HT system by AVP during birth stress may impact its own ongoing functional development as well as affect maturation of cortical target regions, which may increase the risk for psychiatric conditions later on. Author ContributionsE.O. performed and analysed the in vitro electrophysiological experiments, related immunohistochemistry of filled neurons as well as image analysis, B.K. and H.H. conducted and analysed the in vivo juxtacellular electrophysiological recordings and labelling, related immunohistochemistry of labelled neurons and image analysis, H.H. did the multi-channel in vivo electrophysiological recordings and intracerebral injections as well as related histology, H.T-G. analysed the multi-channel in vivo electrophysiological data, B.K. and H.H. performed the tracing experiments, E.O. and H.H. carried out immunohistochemistry related to the tracing experiments, E.O. performed image analysis related to tracing experiments, M.S. performed and analysed AVP immunocytochemistry experiments in neonatal DRN, H.H. and S.E.L. provided resources for the experimental work and supervised the project. H.H. conceptualized and coordinated the project. The manuscript was written by H.H. with significant contributions from all authors.

neuroscience↗

bioRxiv2023

GluK1 kainate receptors are necessary for functional maturation of parvalbumin interneurons regulating amygdala circuit function

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 basolateral 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 the PV phenotype, suggesting a role for GluK1 in dynamic regulation of PV IN maturation state. The PV IN dysfunction in the absence of GluK1 perturbed feedforward inhibition and long-term potentiation (LTP) in the BLA and resulted in developmentally originating changes in the glutamatergic connectivity to BLA principal neurons. 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.

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bioRxiv2022

Activation of TrkB in Parvalbumin interneurons is required for the promotion of reversal learning in spatial and fear memory by antidepressants

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 (LTP) 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 (PNN) 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.

neuroscience↗

bioRxiv2022

Transient developmental increase in cortical projections to amygdala GABAergic neurons contribute to circuit dysfunction following early life stress

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.

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bioRxiv2021

Optical activation of TrkB neurotrophin receptor in mouse ventral hippocampus promotes plasticity and facilitates fear extinction

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.

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bioRxiv2019

Kainate-type of glutamate receptors regulate wiring of intrinsic glutamatergic connectivity in the amygdala

Perturbed information processing in the amygdala has been implicated in developmentally originating neuropsychiatric disorders. However, little is known on the mechanisms that guide formation and refinement of intrinsic connections between amygdaloid nuclei. We demonstrate that the glutamatergic connection from basolateral to central amygdala (BLA-CeA) develops rapidly during the first ten postnatal days, before external inputs underlying amygdala dependent behaviors emerge. During this restricted period of synaptic development, kainate-type of ionotropic glutamate receptors (KARs) are highly expressed in the BLA and tonically activated to regulate glutamate release via a G-protein dependent mechanism. Genetic manipulation of this endogenous KAR activity locally in the newborn LA perturbed development of glutamatergic input to CeA, identifying KARs as a physiological mechanism regulating wiring of the intrinsic glutamatergic circuitry in the amygdala.

neuroscience↗