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Valentina Gigliucci, Jasper Teutsch, Marc Woodbury-Smith, Mirko Luoni, Marta Busnelli, ,
Published: 25 September 2021
Abstract:
Rett syndrome (RTT) is characterized by dysfunction in neuronal excitation/inhibition (E/I) balance, potentially impacting seizure susceptibility via deficits in K+/Cl- cotransporter 2 (KCC2) function. Mice lacking the Methyl-CpG binding protein 2 (MeCP2) recapitulate many symptoms of RTT, and recombinant human insulin-like growth factor-1 (rhIGF-1) restores KCC2 expression and E/I balance in MeCP2 KO mice. However, clinical trial outcomes of rhIGF-1 in RTT have been variable, and increasing its therapeutic efficacy is highly desirable. To this end, the neuropeptide oxytocin (OXT) is promising, as it also critically modulates KCC2 function during early postnatal development. We measured basal KCC2 expression levels in MeCP2 KO mice and identified three key frontal brain regions showing KCC2 alterations in young adult mice but not in postnatal P10 animals. We thus hypothesized that deficits in an IGF-1/OXT signaling crosstalk modulating KCC2 may occur in RTT during postnatal development. Consistently, we detected alterations of IGF-1 receptor (IGF-1R) and OXT receptor (OXTR) levels in those brain areas. rhIGF-1 and OXT treatments in KO mice rescued KCC2 expression in a region-specific and complementary manner. These results suggest that region-selective combinatorial pharmacotherapeutic strategies could be the most effective at normalizing E/I balance in key brain regions subtending the RTT pathophysiology.
Michimasa Toyoshima, Koshiro Mitsui,
Published: 16 September 2021
Neuroscience Letters, Volume 765; https://doi.org/10.1016/j.neulet.2021.136253

The publisher has not yet granted permission to display this abstract.
Published: 20 August 2021
Behavioural Brain Research, Volume 416; https://doi.org/10.1016/j.bbr.2021.113541

The publisher has not yet granted permission to display this abstract.
Alessandra Bertoni, Fabienne Schaller, Roman Tyzio, Stephane Gaillard, Francesca Santini, Marion Xolin, Diabé Diabira, Radhika Vaidyanathan, , Igor Medina, et al.
Published: 21 July 2021
Molecular Psychiatry pp 1-14; https://doi.org/10.1038/s41380-021-01227-6

Abstract:
Oxytocin is an important regulator of the social brain. In some animal models of autism, notably in Magel2 tm1.1Mus -deficient mice, peripheral administration of oxytocin in infancy improves social behaviors until adulthood. However, neither the mechanisms responsible for social deficits nor the mechanisms by which such oxytocin administration has long-term effects are known. Here, we aimed to clarify these oxytocin-dependent mechanisms, focusing on social memory performance. Using in situ hybridization (RNAscope), we have established that Magel2 and oxytocin receptor are co-expressed in the dentate gyrus and CA2/CA3 hippocampal regions involved in the circuitry underlying social memory. Then, we have shown that Magel2 tm1.1Mus -deficient mice, evaluated in a three-chamber test, present a deficit in social memory. Next, in hippocampus, we conducted neuroanatomical and functional studies using immunostaining, oxytocin-binding experiments, ex vivo electrophysiological recordings, calcium imaging and biochemical studies. We demonstrated: an increase of the GABAergic activity of CA3-pyramidal cells associated with an increase in the quantity of oxytocin receptors and of somatostatin interneurons in both DG and CA2/CA3 regions. We also revealed a delay in the GABAergic development sequence in Magel2 tm1.1Mus -deficient pups, linked to phosphorylation modifications of KCC2. Above all, we demonstrated the positive effects of subcutaneous administration of oxytocin in the mutant neonates, restoring hippocampal alterations and social memory at adulthood. Although clinical trials are debated, this study highlights the mechanisms by which peripheral oxytocin administration in neonates impacts the brain and demonstrates the therapeutic value of oxytocin to treat infants with autism spectrum disorders.
Diego Scheggia, , Maria Italia, Filippo La Greca, Elisa Zianni, Alberto Benussi, Barbara Borroni, Monica Di Luca,
Published: 9 July 2021
Brain, Behavior, and Immunity, Volume 97, pp 89-101; https://doi.org/10.1016/j.bbi.2021.07.001

Abstract:
Autoantibodies targeting the GluA3 subunit of AMPA receptors (AMPARs) have been found in patients with Rasmussen’s encephalitis and different types of epilepsy and were associated with the presence of learning and attention deficits. Our group recently identified the presence of anti-GluA3 immunoglobulin G (IgG) in about 25% of patients with frontotemporal dementia (FTD), thus suggesting a novel pathogenetic role also in chronic neurodegenerative diseases. However, the in vivo behavioral, molecular and morphological effects induced these antibodies are still unexplored. We injected anti-GluA3 IgG purified from the serum of FTD patients, or control IgG, in mice by intracerebroventricular infusion. Biochemical analyses showed a reduction of synaptic levels of GluA3-containing AMPARs in the prefrontal cortex (PFC), and not in the hippocampus. Accordingly, animals injected with anti-GluA3 IgG showed significant changes in recognition memory and impairments in social behavior and in social cognitive functions. As visualized by confocal imaging, functional outcomes were paralleled by profound alterations of dendritic spine morphology in the PFC. All observed behavioral, molecular and morphological alterations were transient and not detected 10–14 days from anti-GluA3 IgG injection. Overall, our in vivo preclinical data provide novel insights into autoimmune encephalitis associated with anti-GluA3 IgG and indicate an additional pathological mechanism affecting the excitatory synapses in FTD patients carrying anti-GluA3 IgG that could contribute to clinical symptoms.
, Fani Koukouli, , Cantin Ortiz, Hsin-Lun Kao, Uwe Maskos, ,
Published: 6 July 2021
Abstract:
Preparatory activity in the frontal cortex preceding movement onset is thought to represent a neuronal signature of motor planning. However, how excitatory and inhibitory synaptic inputs to frontal neurons are integrated during movement preparation remains unclear. Here we address this question by performing in vivo whole-cell patch-clamp recordings in the secondary motor cortex (MOs) of head-fixed mice moving on a treadmill. We find that both superficial and deep principal neurons show slowly increasing (~10 s) membrane potential and spike rate ramps preceding the onset of spontaneous, self-paced running periods. By contrast, in animals trained to perform a goal-directed task, both membrane potential and spike ramps are characterized by larger amplitudes and accelerated kinetics during preparation of goal-driven movement. To determine the role of local inhibitory neurons in shaping these task-dependent preparatory signals, we chemogenetically suppressed the activity of specific interneuron subpopulations in untrained animals. Inactivation of parvalbumin-positive (PV+) interneurons leads to depolarized membrane potential ramps with increased amplitudes during preparation of movement, while inactivation of somatostatin-positive (SOM+) interneurons abolishes membrane potential ramps. A computational model of the local MOs circuit shows that SOM+-mediated inhibition of PV+ interneurons in conjunction with recurrent connectivity among the principal neurons can reproduce slow ramping signals, while plasticity of excitatory synapses on SOM+ interneurons can explain the acceleration of these signals in trained animals. Together, our data reveal that local inhibitory neurons play distinct roles in controlling task-dependent preparatory ramping signals when MOs neurons integrate external inputs during motor planning. Highlights Principal neurons in MOs show slow preparatory membrane potential and firing rate ramps preceding the onset of spontaneous, self-paced running periods. In animals trained to perform a goal-directed task, both membrane potential and spike ramps are faster and larger in amplitude. Inactivation of PV+ interneurons disinhibits MOs principal neurons and increases the amplitude of membrane potential ramps, while inactivation of SOM+ interneurons abolishes membrane potential ramps. Our modeling results suggest that the concerted action of external inputs and local inactivation shapes task-dependent preparatory motor signals in MOs neurons.
Shuai Zhang, Shuwei Hu, Wanting Dong, Songqiang Huang, Zhexiao Jiao, Zewen Hu, Shiyun Dai, Yiwen Yi, Xiaohan Gong, Ke Li, et al.
Published: 29 June 2021
Cell Biology and Toxicology pp 1-22; https://doi.org/10.1007/s10565-021-09621-0

The publisher has not yet granted permission to display this abstract.
Published: 11 June 2021
Abstract:
Summary In order to understand ecologically meaningful social behaviors and their neural substrates in humans and other animals, researchers have been using a variety of social stimuli in the laboratory with a goal of extracting specific processes in real-life scenarios. However, certain stimuli may not be sufficiently effective at evoking typical social behaviors and neural responses. Here, we review empirical research employing different types of social stimuli by classifying them into five levels of naturalism. We describe the advantages and limitations while providing selected example studies for each level. We emphasize the important trade-off between experimental control and ecological validity across the five levels of naturalism. Taking advantage of newly emerging tools, such as real-time videos, virtual avatars, and wireless neural sampling techniques, researchers are now more than ever able to adopt social stimuli at a higher level of naturalism to better capture the dynamics and contingency of real-life social interaction.
Seong-Wook Kim, Minsoo Kim,
Current Opinion in Neurobiology, Volume 68, pp 181-189; https://doi.org/10.1016/j.conb.2021.05.002

The publisher has not yet granted permission to display this abstract.
Weronika Barcik, Giulia Chiacchierini, ,
Published: 28 May 2021
Current Opinion in Immunology, Volume 71, pp 46-54; https://doi.org/10.1016/j.coi.2021.05.001

The publisher has not yet granted permission to display this abstract.
, Madeline Klinger, Nana J. Okada,
Seminars in Cell & Developmental Biology, Volume 118, pp 64-72; https://doi.org/10.1016/j.semcdb.2021.04.021

Abstract:
Across species, adolescence is a period of growing independence that is associated with the maturation of cognitive, social, and affective processing. Reorganization of neural circuits within the frontal cortex is believed to contribute to the emergence of adolescent changes in cognition and behavior. While puberty coincides with adolescence, relatively little is known about which aspects of frontal cortex maturation are driven by pubertal development and gonadal hormones. In this review, we highlight existing work that suggests puberty plays a role in the maturation of specific cell types in the medial prefrontal cortex (mPFC) of rodents, and highlight possible routes by which gonadal hormones influence frontal cortical circuit development.
Jorge Luis-Islas, Monica Luna, Benjamin Floran,
Published: 23 April 2021
Abstract:
How do animals experience brain manipulations? Optogenetics has allowed us to manipulate selectively and interrogate neural circuits underlying brain function in health and disease. However, in addition to their evoked physiological functions, it is currently unknown whether mice could perceive arbitrary optogenetic stimulations. To address this issue, mice were trained to report optogenetic stimulations to obtain rewards and avoid punishments. It was found that mice could perceive optogenetic manipulations regardless of the brain area modulated, their rewarding effects, or the stimulation of glutamatergic, GABAergic, and dopaminergic cell types. We named this phenomenon optoception. Our findings reveal that mice’s brains are capable of “monitoring” their self-activity via interoception, opening a new way to introduce information to the brain and control brain-computer interfaces. One Sentence Summary Brain manipulations are perceived
Renad Jabarin, Nina Levy, Yasmin Abergel, Joshua H. Berman, Amir Zag, Shai Netser, ,
Published: 22 April 2021
Translational Psychiatry, Volume 11, pp 1-11; https://doi.org/10.1038/s41398-021-01347-1

Abstract:
In this study we tested the hypothesis that pharmacological modulation of glutamatergic neurotransmission could rescue behavioral deficits exhibited by mice carrying a specific mutation in the Iqsec2 gene. The IQSEC2 protein plays a key role in glutamatergic synapses and mutations in the IQSEC2 gene are a frequent cause of neurodevelopmental disorders. We have recently reported on the molecular pathophysiology of one such mutation A350V and demonstrated that this mutation downregulates AMPA type glutamatergic receptors (AMPAR) in A350V mice. Here we sought to identify behavioral deficits in A350V mice and hypothesized that we could rescue these deficits by PF-4778574, a positive AMPAR modulator. Using a battery of social behavioral tasks, we found that A350V Iqsec2 mice exhibit specific deficits in sex preference and emotional state preference behaviors as well as in vocalizations when encountering a female mouse. The social discrimination deficits, but not the impaired vocalization, were rescued with a single dose of PF-4778574. We conclude that social behavior deficits associated with the A350V Iqsec2 mutation may be rescued by enhancing AMPAR mediated synaptic transmission.
Enrica Paradiso, ,
Published: 20 March 2021
Current Opinion in Neurobiology, Volume 68, pp 107-115; https://doi.org/10.1016/j.conb.2021.02.005

Abstract:
The neural basis of empathy and prosociality has received much interest over the past decades. Neuroimaging studies localized a network of brain regions with activity that correlates with empathy. Here, we review how the emergence of rodent and nonhuman primate models of empathy-related phenomena supplements human lesion and neuromodulation studies providing evidence that activity in several nodes is necessary for these phenomena to occur. We review proof that (i) affective states triggered by the emotions of others, (ii) motivations to act in ways that benefit others, and (iii) emotion recognition can be altered by perturbing brain activity in many nodes identified by human neuroimaging, with strongest evidence for the cingulate and the amygdala. We also include evidence that manipulations of the oxytocin system and analgesics can have such effects, the latter providing causal evidence for the recruitment of an individual's own nociceptive system to feel with the pain of others.
Published: 4 February 2021
Current Opinion in Neurobiology, Volume 68, pp 67-75; https://doi.org/10.1016/j.conb.2021.01.007

The publisher has not yet granted permission to display this abstract.
Anna D Zych,
Published: 3 February 2021
Current Opinion in Neurobiology, Volume 68, pp 57-66; https://doi.org/10.1016/j.conb.2021.01.003

Abstract:
What are emotions and how should we study them? These questions give rise to ongoing controversy amongst scientists in the fields of neuroscience, psychology and philosophy, and have resulted in different views on emotions [1, 2, 3, 4, 5, 6]. In this review, we define emotions as functional states that bear essential roles in promoting survival and thus have emerged through evolution. Emotions trigger behavioral, somatic, hormonal, and neurochemical reactions, referred to as expressions of emotion. We discuss recent studies on emotion expression across species and highlight emerging common principles. We argue that detailed and multidimensional analyses of emotion expressions are key to develop biology-based definitions of emotions and to reveal their neuronal underpinnings.
Published: 27 January 2021
Molecular Brain, Volume 14, pp 1-13; https://doi.org/10.1186/s13041-021-00731-8

Abstract:
Disrupted GABAergic neurons have been extensively described in brain tissues from individuals with autism spectrum disorder (ASD) and animal models for ASD. However, the contribution of these aberrant inhibitory neurons to autism-related behavioral phenotypes is not well understood. We examined ASD-related behaviors in mice with conditional Pten knockout in parvalbumin (PV)-expressing or somatostatin (Sst)-expressing neurons, two common subtypes of GABAergic neurons. We found that mice with deletion of Pten in either PV-neurons or Sst-neurons displayed social deficits, repetitive behaviors and impaired motor coordination/learning. In addition, mice with one copy of Pten deletion in PV-neurons exhibited hyperlocomotion in novel open fields and home cages. We also examined anxiety behaviors and found that mice with Pten deletion in Sst-neurons displayed anxiety-like behaviors, while mice with Pten deletion in PV-neurons exhibited anxiolytic-like behaviors. These behavioral assessments demonstrate that Pten knockout in the subtype of inhibitory neurons sufficiently gives rise to ASD-core behaviors, providing evidence that both PV- and Sst-neurons may play a critical role in ASD symptoms.
Natanja F. Peen, Natalia Duque-Wilckens,
Published: 20 January 2021
Hormones and Behavior, Volume 129; https://doi.org/10.1016/j.yhbeh.2021.104933

The publisher has not yet granted permission to display this abstract.
, Yann Dromard, Gilles Guillon, Aleksandra Olma, Maurice Manning, Françoise Muscatelli, Michel G. Desarménien,
Journal of Clinical Investigation, Volume 131; https://doi.org/10.1172/jci144450

Abstract:
Intellectual and social disabilities are common comorbidities in adolescents and adults with MAGEL2 gene deficiency characterizing the Prader-Willi and Schaaf-Yang neurodevelopmental syndromes. The cellular and molecular mechanisms underlying the risk for autism in these syndromes are not understood. We ask whether vasopressin functions are altered by MAGEL2 deficiency and whether a treatment with vasopressin can alleviate the disabilities of social behavior. We used Magel2 knockout mice (adult males) combined with optogenetic or pharmacological tools to characterize disease modifications in the vasopressinergic brain system and monitor its impact on neurophysiological and behavioral functions. We find that the activation of vasopressin neurons and its projections in the lateral septum are inappropriate to perform a social habituation/discrimination task. Mechanistically, the lack of vasopressin impedes the deactivation of somatostatin neurons in the lateral septum, which predicts social discrimination deficits. Correction of vasopressin septal content by administration or optogenetic stimulation of projecting axons suppressed the activity of somatostatin neurons and ameliorated social behavior. This preclinical study identifies vasopressin in the lateral septum as a key factor in the pathophysiology.
Toni-Lee Sterley,
Published: 9 January 2021
Current Opinion in Neurobiology, Volume 68, pp 44-51; https://doi.org/10.1016/j.conb.2020.12.007

The publisher has not yet granted permission to display this abstract.
Jun Wang, Yuanyuan Tian, Ling-Hui Zeng,
Frontiers in Cellular Neuroscience, Volume 14; https://doi.org/10.3389/fncel.2020.611732

Abstract:
Social fear and avoidance of social partners and social situations represent the core behavioral symptom of Social Anxiety Disorder (SAD), a prevalent psychiatric disorder worldwide. The pathological mechanism of SAD remains elusive and there are no specific and satisfactory therapeutic options currently available. With the development of appropriate animal models, growing studies start to unravel neuronal circuit mechanisms underlying social fear, and underscore a fundamental role of the prefrontal cortex (PFC). Prefrontal cortical functions are implemented by a finely wired microcircuit composed of excitatory principal neurons (PNs) and diverse subtypes of inhibitory interneurons (INs). Disinhibition, defined as a break in inhibition via interactions between IN subtypes that enhances the output of excitatory PNs, has recently been discovered to serve as an efficient strategy in cortical information processing. Here, we review the rodent animal models of social fear, the prefrontal IN diversity, and their circuits with a particular emphasis on a novel disinhibitory microcircuit mediated by somatostatin-expressing INs in gating social fear behavior. The INs subtype distinct and microcircuit-based mechanism advances our understanding of the etiology of social fear and sheds light on developing future treatment of neuropsychiatric disorders associated with social fear.
, Fabienne Schaller, Roman Tyzio, Stephane Gaillard, Francesca Santini, Marion Xolin, Diabé Diabira, Radhika Vaidyanathan, , , et al.
Published: 21 September 2020
Abstract:
Oxytocin is a master regulator of the social brain. In some animal models of autism, notably in Magel2 tm1.1Mus -deficient mice, peripheral administration of oxytocin in infancy improves social behaviors until adulthood. However, neither the mechanisms responsible for social deficits nor the mechanisms by which such oxytocin administration has long-term effects are known. Here, we aimed to clarify these oxytocin-dependent mechanisms focusing on social memory performance. We showed that Magel2tm1.1Mus-deficient mice present a deficit in social memory and studied the hippocampal circuits underlying this memory. We showed a co-expression of Magel2 and oxytocin-receptor in the dentate gyrus and CA2/CA3 hippocampal regions. Then, we demonstrated: an increase of the GABAergic activity of CA3-pyramidal cells associated with an increase in the quantity of oxytocin-receptors and of somatostatin interneurons. We also revealed a delay in the GABAergic development sequence in Magel2tm1.1Mus -deficient pups, linked to phosphorylation modifications of KCC2. Above all, we demonstrated the positive effects of subcutaneous administration of oxytocin in the mutant neonates, restoring neuronal alterations and social memory. Although clinical trials are debated, this study highlights the mechanisms by which peripheral oxytocin-administration in neonates impacts the brain and demonstrates the therapeutic value of oxytocin to treat infants with autism spectrum disorders.
, Meghan A. Collins, , Kacey Fang, Jingwei Li, Tong He, , ,
Proceedings of the National Academy of Sciences, Volume 117, pp 25138-25149; https://doi.org/10.1073/pnas.2008004117

Abstract:
Major depressive disorder emerges from the complex interactions of biological systems that span genes and molecules through cells, networks, and behavior. Establishing how neurobiological processes coalesce to contribute to depression requires a multiscale approach, encompassing measures of brain structure and function as well as genetic and cell-specific transcriptional data. Here, we examine anatomical (cortical thickness) and functional (functional variability, global brain connectivity) correlates of depression and negative affect across three population-imaging datasets: UK Biobank, Brain Genomics Superstruct Project, and Enhancing NeuroImaging through Meta Analysis (ENIGMA; combined n ≥ 23,723). Integrative analyses incorporate measures of cortical gene expression, postmortem patient transcriptional data, depression genome-wide association study (GWAS), and single-cell gene transcription. Neuroimaging correlates of depression and negative affect were consistent across three independent datasets. Linking ex vivo gene down-regulation with in vivo neuroimaging, we find that transcriptional correlates of depression imaging phenotypes track gene down-regulation in postmortem cortical samples of patients with depression. Integrated analysis of single-cell and Allen Human Brain Atlas expression data reveal somatostatin interneurons and astrocytes to be consistent cell associates of depression, through both in vivo imaging and ex vivo cortical gene dysregulation. Providing converging evidence for these observations, GWAS-derived polygenic risk for depression was enriched for genes expressed in interneurons, but not glia. Underscoring the translational potential of multiscale approaches, the transcriptional correlates of depression-linked brain function and structure were enriched for disorder-relevant molecular pathways. These findings bridge levels to connect specific genes, cell classes, and biological pathways to in vivo imaging correlates of depression.
Caroline J. Smith, Marcy A. Kingsbury, Julia E. Dziabis, Richa Hanamsagar, Karen E. Malacon, Jessica N. Tran, Haley A. Norris, Mary Gulino, Evan A. Bordt,
Published: 26 August 2020
Brain, Behavior, and Immunity, Volume 90, pp 332-345; https://doi.org/10.1016/j.bbi.2020.08.013

The publisher has not yet granted permission to display this abstract.
Saurav Seshadri, Daniel J. Hoeppner,
Published: 23 July 2020
Frontiers in Psychiatry, Volume 11; https://doi.org/10.3389/fpsyt.2020.00713

Abstract:
The past 5 years have seen a sharp increase in the number of studies using calcium imaging in behaving rodents. These studies have helped identify important roles for individual cells, brain regions, and circuits in some of the core behavioral phenotypes of psychiatric disorders, such as schizophrenia and autism, and have characterized network dysfunction in well-established models of these disorders. Since rescuing clinically relevant behavioral deficits in disease model mice remains a foundation of preclinical CNS research, these studies have the potential to inform new therapeutic approaches targeting specific cell types or projections, or perhaps most importantly, the network-level context in which neurons function. In this mini-review, we will provide a brief overview of recent insights into psychiatric disease-associated mouse models and behavior paradigms, focusing on those achieved by cellular resolution imaging of calcium dynamics in neural populations. We will then discuss how these experiments can support efforts within the pharmaceutical industry, such as target identification, assay development, and candidate screening and validation. Calcium imaging is uniquely capable of bridging the gap between two of the key resources that currently enable CNS drug discovery: genomic and transcriptomic data from human patients, and translatable, population-resolution measures of brain activity (such as fMRI and EEG). Applying this knowledge could yield real value to patients in the near future.
Jiaxun Nie, Xiaoyan Wei, Xing Xu, Nanqin Li, Yuehan Li, Yonghua Zhao, Yun Guan, Feifei Ge, Xiaowei Guan
Published: 19 July 2020
The FASEB Journal, Volume 34, pp 11913-11924; https://doi.org/10.1096/fj.202000346rr

Abstract:
We recently found that adolescent cocaine exposure (ACE) resulted in an enhancement of the γ‐aminobutyric acid (GABA) neurotransmitter system in the prelimbic cortex (PrL) of adult mice. Here, we aim to further investigate the role of GABAergic transmission, especially parvalbumin (PV) interneurons within PrL in the development of ACE‐induced anxiety‐like behavior, and to assess whether and how electro‐acupuncture (EA) therapeutically manage the ACE‐induced abnormal behaviors in adulthood. ACE mice exhibited the enhanced anxiety‐like behaviors in their adulthood, accompanied by increased GABAergic transmission and PV interneurons in PrL. Chemogenetic blocking PV interneurons in PrL alleviated ACE‐enhanced anxiety‐like behaviors in mice. Importantly, 37‐day EA treatments (mixture of 2 Hz/100 Hz, 1 mA, 30 minutes once a day) at the acupoints of Yintang (GV29) and Baihui (GV20) also alleviated ACE‐induced anxiety‐like behaviors, and rescued ACE‐impaired GABAergic neurotransmitter system and PV interneurons in PrL. In parallel, EA treatments further suppressed the activities of pyramidal neurons in PrL, suggesting that EA treatments seem to perform it beneficial effects on the ACE‐induced abnormal emotional behaviors by “calming down” the whole PrL. Collectively, these findings revealed that hyper‐function of GABAergic transmission, especially mediating by PV interneurons in PrL may be key etiology underlying ACE‐induced anxiety‐like behaviors. At least by normalizing the function of GABAergic and PV interneurons, EA may represent a promising therapeutic strategy for managing adolescent substance use‐related emotional disorders.
, , Berta Anuncibay Soto, Mikal Vicente, , Panagiotis Giannos, Andawei Miao, Bryan Hsieh, , , et al.
Published: 2 July 2020
Abstract:
Animals undertake specific behaviors before sleep. Little is known about whether these innate behaviors, such as nest building, are actually an intrinsic part of the sleep-inducing circuitry. We found, using activity-tagging genetics, that mouse prefrontal cortex (PFC) somatostatin/GABAergic (SOM/GABA) neurons, which become activated during sleep deprivation, induce nest building when opto-activated. These tagged neurons induce sustained global NREM sleep if their activation is prolonged metabotropically. Sleep-deprivation-tagged PFC SOM/GABA neurons have long-range projections to the lateral preoptic (LPO) and lateral hypothalamus (LH). Local activation of tagged PFC SOM/GABA terminals in LPO and the LH induced nesting and NREM sleep respectively. Our findings provide a circuit link for how the PFC responds to sleep deprivation by coordinating sleep preparatory behavior and subsequent sleep.
Krisztina Kordás, Ágnes Kis-Varga, Anita Varga, Herman Eldering, Ronald Bulthuis, Balázs Lendvai, György Lévay,
Journal of Neuroscience Methods, Volume 343; https://doi.org/10.1016/j.jneumeth.2020.108841

The publisher has not yet granted permission to display this abstract.
Sébastien Valverde, Marie Vandecasteele, Charlotte Piette, Willy Derousseaux, , Asier Aristieta Arbelaiz, Jonathan Touboul, Bertrand Degos,
Published: 13 May 2020
Nature Communications, Volume 11, pp 1-17; https://doi.org/10.1038/s41467-020-16046-6

Abstract:
Deep brain stimulation (DBS) of the subthalamic nucleus is a symptomatic treatment of Parkinson’s disease but benefits only to a minority of patients due to stringent eligibility criteria. To investigate new targets for less invasive therapies, we aimed at elucidating key mechanisms supporting deep brain stimulation efficiency. Here, using in vivo electrophysiology, optogenetics, behavioral tasks and mathematical modeling, we found that subthalamic stimulation normalizes pathological hyperactivity of motor cortex pyramidal cells, while concurrently activating somatostatin and inhibiting parvalbumin interneurons. In vivo opto-activation of cortical somatostatin interneurons alleviates motor symptoms in a parkinsonian mouse model. A computational model highlights that a decrease in pyramidal neuron activity induced by DBS or by a stimulation of cortical somatostatin interneurons can restore information processing capabilities. Overall, these results demonstrate that activation of cortical somatostatin interneurons may constitute a less invasive alternative than subthalamic stimulation.
Kazuhiko Yamamuro, Hiroki Yoshino, Yoichi Ogawa, Kazuya Okamura, Yosuke Nishihata, Manabu Makinodan, Yasuhiko Saito, Toshifumi Kishimoto
Frontiers in Cellular Neuroscience, Volume 14; https://doi.org/10.3389/fncel.2020.00105

Abstract:
During brain development, the design of primary neural networks is primarily determined by environmental stimuli after their formation. In particular, the juvenile period is critical, during which neuronal circuits that consist of both excitatory and inhibitory neurons are remodeled by experience. Social isolation during the juvenile period profoundly affects brain development and contributes to the development of psychiatric disorders. We previously reported that 2 weeks of social isolation after weaning reduced excitatory synaptic inputs and intrinsic excitability in a subtype of layer 5 pyramidal cells, which we defined as prominent h-current (PH) cells, in the medial prefrontal cortex (mPFC) in mice. However, it remains unclear how juvenile social isolation affects inhibitory neuronal circuits that consist of pyramidal cells and interneurons. We found that 2 weeks of social isolation after weaning increased inhibitory synaptic inputs exclusively onto PH cells with a concomitant deterioration of action potential properties. Although social isolation did not alter the inhibitory synaptic release mechanisms or the number of inhibitory functional synapses on PH cells, we found that it increased the intrinsic excitability of fast-spiking (FS) interneurons with less excitatory synaptic inputs and more h-current. Our findings indicate that juvenile social isolation enhances the activity of inhibitory neuronal circuits in the mPFC.
Published: 2 May 2020
Abstract:
Decreases in social behavior are a hallmark aspect of acute “sickness behavior” in response to infection. However, immune insults that occur during the perinatal period may have long-lasting consequences for adult social behavior by impacting the developmental organization of underlying neural circuits. Microglia, the resident immune cells of the central nervous system, are sensitive to immune stimulation and play a critical role in the developmental sculpting of neural circuits, making them likely mediators of this process. Here, we investigated the impact of a postnatal day (PND) 4 lipopolysaccharide (LPS) challenge on social behavior in adult mice. Somewhat surprisingly, neonatal LPS treatment decreased sociability in adult female, but not male mice. LPS-treated females also displayed reduced social interaction and social memory in a social discrimination task as compared to saline-treated females. Somatostatin (SST) interneurons within the anterior cingulate cortex (ACC) have recently been suggested to modulate a variety of social behaviors. Interestingly, the female-specific changes in social behavior observed here were accompanied by an increase in SST interneuron number in the ACC. Finally, these changes in social behavior and SST cell number do not appear to depend on microglial inflammatory signaling, because microglia-specific genetic knock-down of myeloid differentiation response protein 88 (MyD88; the removal of which prevents LPS from increasing proinflammatory cytokines such as TNFα and IL-1β) did not prevent these LPS-induced changes. This study provides novel evidence for enduring effects of neonatal immune activation on social behavior and SST interneurons in females, independent of microglial inflammatory signaling.
Sangyep Shin, Andrea Santi,
Published: 18 April 2020
Abstract:
Disrupted GABAergic neurons have been extensively described in brain tissues from individuals with autism spectrum disorder (ASD) and animal models for ASD. However, the contribution of these aberrant inhibitory neurons to autism-related behavioral phenotypes is not well understood. We examined ASD-related behaviors in mice with conditional Pten knockout in parvalbumin (PV)-expressing or somatostatin (Sst)-expressing neurons, two common subtypes of GABAergic neurons. We found that mice with deletion of Pten in either PV-neurons or Sst-neurons displayed social deficits, repetitive behaviors and impaired motor coordination/learning. In addition, mice with one copy of Pten deletion in PV-neurons exhibited hyperlocomotion in novel open fields and home cages. We also examined anxiety behaviors and found that mice with Pten deletion in Sst-neurons displayed anxiety-like behaviors, while mice with Pten deletion in PV-neurons exhibited anxiolytic-like behaviors. These behavioral assessments demonstrate that Pten knockout in the subtype of inhibitory neurons sufficiently gives rise to ASD-core behaviors, providing evidence that both PV- and Sst-neurons may play a critical role in ASD symptoms.
, Augustine Attah, , Cindy M. Pinhal, Valeria Gazzola,
Published: 5 March 2020
Current Biology, Volume 30, pp 949-961.e7; https://doi.org/10.1016/j.cub.2020.01.017

Abstract:
Summary Empathy, the ability to share another individual's emotional state and/or experience, has been suggested to be a source of prosocial motivation by attributing negative value to actions that harm others. The neural underpinnings and evolution of such harm aversion remain poorly understood. Here, we characterize an animal model of harm aversion in which a rat can choose between two levers providing equal amounts of food but one additionally delivering a footshock to a neighboring rat. We find that independently of sex and familiarity, rats reduce their usage of the preferred lever when it causes harm to a conspecific, displaying an individually varying degree of harm aversion. Prior experience with pain increases this effect. In additional experiments, we show that rats reduce the usage of the harm-inducing lever when it delivers twice, but not thrice, the number of pellets than the no-harm lever, setting boundaries on the magnitude of harm aversion. Finally, we show that pharmacological deactivation of the anterior cingulate cortex, a region we have shown to be essential for emotional contagion, reduces harm aversion while leaving behavioral flexibility unaffected. This model of harm aversion might help shed light onto the neural basis of psychiatric disorders characterized by reduced harm aversion, including psychopathy and conduct disorders with reduced empathy, and provides an assay for the development of pharmacological treatments of such disorders. Video Abstract
Diego Scheggia,
Published: 1 March 2020
Current Biology, Volume 30; https://doi.org/10.1016/j.cub.2020.01.093

Abstract:
SummaryAre rats willing to avoid causing suffering in other rats? A new study shows that rats might change their behaviour if it is harmful to others.
, Meghan A Collins, , Kacey Fang, Jingwei Li, , , ,
Published: 11 February 2020
Abstract:
Major depressive disorder emerges from the complex interactions of biological systems that span across genes and molecules through cells, circuits, networks, and behavior. Establishing how neurobiological processes coalesce to contribute to the onset and maintenance of depression requires a multi-scale approach, encompassing measures of brain structure and function as well as genetic and cell-specific genomic data. Here, we examined anatomical (cortical thickness) and functional (functional variability, global brain connectivity) correlates of depression and negative affect across three population-imaging datasets: UK Biobank, Genome Superstruct Project, and ENIGMA (combined N≥23,723). Integrative analyses incorporated measures of cortical gene expression, post-mortem patient transcriptional data, depression GWAS, and single-cell transcription. Neuroimaging correlates of depression and negative affect were consistent across the three independent datasets. Linking ex-vivo gene downregulation with in-vivo neuroimaging, we found that genomic correlates of depression-linked neuroimaging phenotypes tracked gene downregulation in post-mortem cortical tissue samples of patients with depression. Integrated analysis of single-cell and Allen Human Brain Atlas expression data implicated somatostatin interneurons and astrocytes as consistent cell associates of depression, through both in-vivo imaging and ex-vivo cortical gene dysregulation. Providing converging evidence for these observations, GWAS derived polygenic risk for depression was enriched for genes expressed in interneurons, but not glia. Underscoring the translational potential of multi-scale approaches, the genomic correlates of depression-linked brain function and structure were enriched for known and novel disorder relevant molecular pathways. These findings bridge across levels to connect specific genes, cell classes, and biological pathways to in-vivo imaging correlates of depression.
, Sebastiano Alfio Torrisi,
Published: 1 January 2020
BIO-PROTOCOL, Volume 10; https://doi.org/10.21769/bioprotoc.3664

Abstract:
Working memory abnormalities involving the prefrontal cortex (PFC) dramatically contribute to poor functional outcomes in patients with schizophrenia and still represent an unmet therapeutic need. Studies in rodents might provide essential tools to understand the mechanisms underlying PFC-dependent working memory dysfunctions, as well as precious tools for genetic and pharmacological testing. However, proper tests assessing working memory and sensitive to PFC-dependent functions must be used. In this regard, the discrete paired-trial variable-delay T-maze task, equivalent to delayed non-match to sample tasks used in humans, has proved to be an effective paradigm to test PFC-dependent working memory dysfunctions with high predictive validity in human studies.
Published: 16 December 2019
Nature Neuroscience, Volume 23, pp 3-4; https://doi.org/10.1038/s41593-019-0557-2

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