Modulation of prefrontal cortex excitation/inhibition balance rescues social behavior inCNTNAP2-deficient mice

AbstractAutism spectrum disorder (ASD) is a developmental disorder with no effective pharmacological treatments so far. Gut microbiota has been suggested to contribute to autistic symptoms. However, the key genes and the mechanisms linking gut microbiota and brain dysfunctions in ASD are still unclear. Here, we found deletion of EphB6, an ASD-associated candidate gene, induced dysregulated gut microbiota and autism-like behavior in mice. More importantly, transplanting fecal microbiota from EphB6-deficient mice resulted in disturbed gut microbiota and autism-like behavior in antibiotics-treated C57BL/6J mice. Meanwhile, transplanting fecal microbiota from wild-type mice ameliorated disturbed gut microbiota and autism-like behavior in mice with deletion of EphB6. At the metabolic levels, dysregulated gut microbiota led to vitamin B6 and dopamine defects in EphB6-deficient mice. At the cellular levels, excitation/inhibition (E/I) imbalance in medial prefrontal cortex was induced by gut microbiota-mediated defects of vitamin B6 metabolism in EphB6-deficient mice. Our study uncovers a key role for EphB6 in regulation of social behavior by gut microbiota-mediated vitamin B6 metabolism, dopamine synthesis and E/I balance, suggesting a new strategy for treatment of ASD patients.

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Ibotenic acid induced lesions impair the modulation of dendritic spine plasticity in the prefrontal cortex and amygdala, a phenomenon that underlies working memory and social behavior

European Journal of Pharmacology ◽

10.1016/j.ejphar.2021.173883 ◽

2021 ◽

Vol 896 ◽

pp. 173883

Author(s):

Néstor I. Martínez-Torres ◽

Nallely Vázquez-Hernández ◽

Fabiola L. Martín-Amaya-Barajas ◽

Mario Flores-Soto ◽

Ignacio González-Burgos

Keyword(s):

Working Memory ◽

Prefrontal Cortex ◽

Social Behavior ◽

Dendritic Spine ◽

Ibotenic Acid ◽

Spine Plasticity

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Combined social and spatial coding in a descending projection from the prefrontal cortex

10.1101/155929 ◽

2017 ◽

Cited By ~ 2

Author(s):

M. Murugan ◽

M. Park ◽

J. Taliaferro ◽

H.J. Jang ◽

J. Cox ◽

...

Keyword(s):

Prefrontal Cortex ◽

Social Behavior ◽

Spatial Information ◽

Spatial Association ◽

Well Being ◽

Unique Contribution ◽

Social Investigation ◽

Spatial Coding ◽

Socially Motivated ◽

Spatial Locations

Social interactions are crucial to the survival and well-being of all mammals, including humans. Although the prelimbic cortex (PL, part of medial prefrontal cortex) has been implicated in social behavior, it is not clear which neurons are relevant, nor how they contribute. We found that the PL contains anatomically and molecularly distinct subpopulations of neurons that target 3 downstream regions that have been implicated in social behavior: the nucleus accumbens (NAc), the amygdala, and the ventral tegmental area. Activation of NAc-projecting PL neurons (PL-NAc), but not the other subpopulations, decreased preference for a social target, suggesting an unique contribution of this population to social behavior. To determine what information PL-NAc neurons convey, we recorded selectively from them, and found that individual neurons were active during social investigation, but only in specific spatial locations. Spatially-specific inhibition of these neurons prevented the formation of a social-spatial association at the inhibited location. In contrast, spatially nonspecific inhibition did not affect social behavior. Thus, the unexpected combination of social and spatial information within the PL-NAc population appears to support socially motivated behavior by enabling the formation of social-spatial associations.

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Impaired Perception of Unintentional Transgression of Social Norms after Prefrontal Cortex Damage: Relationship to Decision Making, Emotion Recognition, and Executive Functions

Archives of Clinical Neuropsychology ◽

10.1093/arclin/acab078 ◽

2021 ◽

Author(s):

Riadh Ouerchefani ◽

Naoufel Ouerchefani ◽

Mohamed Riadh Ben Rejeb ◽

Didier Le Gall

Keyword(s):

Decision Making ◽

Prefrontal Cortex ◽

Social Behavior ◽

Theory Of Mind ◽

Social Norms ◽

Executive Functions ◽

Emotion Recognition ◽

Iowa Gambling Task ◽

Gambling Task ◽

Basic Emotions

Abstract Objective Patients with prefrontal cortex damage often transgress social rules and show lower accuracy in identifying and explaining inappropriate social behavior. The objective of this study was to examine the relationship between the ability to perceive other unintentional transgressions of social norms and both decision making and emotion recognition as these abilities are critical for appropriate social behavior. Method We examined a group of patients with focal prefrontal cortex damage (N = 28) and a group of matched control participants (N = 28) for their abilities to detect unintentional transgression of social norms using the “Faux-Pas” task of theory of mind, to make advantageous decisions on the Iowa gambling task, and to recognize basic emotions on the Ekman facial affect test. Results The group of patients with frontal lobe damage was impaired in all of these tasks compared with control participants. Moreover, all the “Faux-Pas”, Iowa gambling, and emotion recognition tasks were significantly associated and predicted by executive measures of inhibition, flexibility, or planning. However, only measures from the Iowa gambling task were associated and predicted performance on the “Faux-Pas” task. These tasks were not associated with performance in recognition of basic emotions. These findings suggest that theory of mind, executive functions, and decision-making abilities act in an interdependent way for appropriate social behavior. However, theory of mind and emotion recognition seem to have distinct but additive effects upon social behavior. Results from VLSM analysis also corroborate these data by showing a partially overlapped prefrontal circuitry underlying these cognitive domains.

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Disturbed Prefrontal Cortex Activity in the Absence of Schizophrenia-Like Behavioral Dysfunction in Arc/Arg3.1 Deficient Mice

Journal of Neuroscience ◽

10.1523/jneurosci.0623-19.2019 ◽

2019 ◽

Vol 39 (41) ◽

pp. 8149-8163 ◽

Cited By ~ 1

Author(s):

Xiaoyan Gao ◽

Jasper Grendel ◽

Mary Muhia ◽

Sergio Castro-Gomez ◽

Ute Süsens ◽

...

Keyword(s):

Prefrontal Cortex ◽

Behavioral Dysfunction ◽

Deficient Mice

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Perinatal THC exposure via lactation induces lasting alterations to social behavior and prefrontal cortex function in rats at adulthood

Neuropsychopharmacology ◽

10.1038/s41386-020-0716-x ◽

2020 ◽

Vol 45 (11) ◽

pp. 1826-1833

Author(s):

Andrew F. Scheyer ◽

Milene Borsoi ◽

Anne-Laure Pelissier- Alicot ◽

Olivier J. J. Manzoni

Keyword(s):

Prefrontal Cortex ◽

Social Behavior

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Chemogenetic Activation of Prefrontal Cortex in Shank3-Deficient Mice Ameliorates Social Deficits, NMDAR Hypofunction, and Sgk2 Downregulation

iScience ◽

10.1016/j.isci.2019.06.014 ◽

2019 ◽

Vol 17 ◽

pp. 24-35 ◽

Cited By ~ 4

Author(s):

Luye Qin ◽

Kaijie Ma ◽

Zhen Yan

Keyword(s):

Prefrontal Cortex ◽

Social Deficits ◽

Deficient Mice

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Microbiota-driven transcriptional changes in prefrontal cortex override genetic differences in social behavior

eLife ◽

10.7554/elife.13442 ◽

2016 ◽

Vol 5 ◽

Cited By ~ 118

Author(s):

Mar Gacias ◽

Sevasti Gaspari ◽

Patricia-Mae G Santos ◽

Sabrina Tamburini ◽

Monica Andrade ◽

...

Keyword(s):

Gene Expression ◽

Prefrontal Cortex ◽

Social Behavior ◽

Gut Microbiota ◽

Nod Mice ◽

Mouse Strains ◽

Social Avoidance ◽

Nonobese Diabetic ◽

Gene Environment ◽

Transcriptional Changes

Gene-environment interactions impact the development of neuropsychiatric disorders, but the relative contributions are unclear. Here, we identify gut microbiota as sufficient to induce depressive-like behaviors in genetically distinct mouse strains. Daily gavage of vehicle (dH2O) in nonobese diabetic (NOD) mice induced a social avoidance behavior that was not observed in C57BL/6 mice. This was not observed in NOD animals with depleted microbiota via oral administration of antibiotics. Transfer of intestinal microbiota, including members of the Clostridiales, Lachnospiraceae and Ruminococcaceae, from vehicle-gavaged NOD donors to microbiota-depleted C57BL/6 recipients was sufficient to induce social avoidance and change gene expression and myelination in the prefrontal cortex. Metabolomic analysis identified increased cresol levels in these mice, and exposure of cultured oligodendrocytes to this metabolite prevented myelin gene expression and differentiation. Our results thus demonstrate that the gut microbiota modifies the synthesis of key metabolites affecting gene expression in the prefrontal cortex, thereby modulating social behavior.

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Maternal Separation Modifies the Activity of Social Processing Brain Nuclei Upon Social Novelty Exposure

Frontiers in Behavioral Neuroscience ◽

10.3389/fnbeh.2021.651263 ◽

2021 ◽

Vol 15 ◽

Author(s):

Sara Mejía-Chávez ◽

Arturo Venebra-Muñoz ◽

Fabio García-García ◽

Aleph Alejandro Corona-Morales ◽

Arturo Enrique Orozco-Vargas

Keyword(s):

Prefrontal Cortex ◽

Nucleus Accumbens ◽

Social Behavior ◽

Medial Prefrontal Cortex ◽

Paraventricular Nucleus ◽

Maternal Separation ◽

Lateral Septum ◽

Medial Amygdala ◽

Physiological Basis ◽

Brain Nuclei

Maternal separation has been shown to disrupt proper brain development and maturation, having profound consequences on the neuroendocrine systems in charge of the stress response, and has been shown to induce behavioral and cognitive abnormalities. At the behavioral level, maternal separation has been shown to increase offensive play-fighting in juvenile individuals and reduce social interest in adulthood. Since most of the studies that have evaluated the consequences of maternal separation on social behavior have focused on behavioral analysis, there is a need for a further understanding of the neuronal mechanisms underlying the changes in social behavior induced by maternal separation. Therefore, the aim of the present research was to assess the long-term effects of maternal separation on social interaction behavior and to assess the activity of several brain regions involved in the processing of social cues and reward upon social novelty exposure, using c-Fos immunohistochemistry as a marker of neuronal activity. Male Wistar rats were subjected to 4 h maternal separation during the neonatal period, 9:00 h–13:00 h from postnatal day 1 to 21, and exposed to social novelty during adulthood. After social novelty exposure, brains were fixed and coronal sections of the medial amygdala, lateral septum (LS), paraventricular nucleus of the hypothalamus, nucleus accumbens, and medial prefrontal cortex were obtained for c-Fos immunohistochemistry. Maternally separated rats spent less time investigating the novel peer, suggesting that maternal separation reduces social approach motivation. Furthermore, maternal separation reduced the number of c-Fos positive cells of the medial amygdala, paraventricular nucleus of the hypothalamus, LS, nucleus accumbens, and medial prefrontal cortex upon social novelty exposure. These findings suggest that maternal separation can reduce the plastic capacity of several brain nuclei, which constitute a physiological basis for the emergence of behavioral disorders presented later in life reported to be linked to early life adversity.

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Parvalbumin interneuron dysfunction in a thalamus - prefrontal cortex circuit in Disc1 deficiency mice

10.1101/054759 ◽

2016 ◽

Author(s):

Kristen Delevich ◽

Hanna Jaaro-Peled ◽

Mario Penzo ◽

Akira Sawa ◽

Bo Li

Keyword(s):

Prefrontal Cortex ◽

Mouse Models ◽

Pyramidal Neurons ◽

Neural Circuit ◽

Gaba Release ◽

Parvalbumin Interneurons ◽

Parvalbumin Interneuron ◽

Inhibitory Circuit ◽

Circuit Function ◽

Deficient Mice

AbstractTwo of the most consistent findings across disrupted-in-schizophrenia-1 (DISC1) mouse models are impaired working memory and reduced number or function of parvalbumin interneurons within the prefrontal cortex. While these findings suggest parvalbumin interneuron dysfunction in DISC1-related pathophysiology, to date, cortical inhibitory circuit function has not been investigated in depth in DISC1 deficiency mouse models. Here we assessed the function of a feedforward circuit between the mediodorsal thalamus (MD) and the medial prefrontal cortex (mPFC) in mice harboring a deletion in one allele of the Disc1 gene. We found that the inhibitory drive onto layer 3 pyramidal neurons in the mPFC was significantly reduced in the Disc1 deficient mice. This reduced inhibition was accompanied by decreased GABA release from local parvalbumin, but not somatostatin, inhibitory interneurons, and by impaired feedforward inhibition in the MD-mPFC circuit. Our results reveal a cellular mechanism by which deficiency in DISC1 causes neural circuit dysfunction frequently implicated in psychiatric disorders.

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