A molecularly defined orbitofrontal cortical neuron population controls compulsive-like behavior, but not inflexible choice or habit.

Habits are familiar behaviors triggered by cues, not outcome predictability, and are insensitive to changes in the environment. They are adaptive under many circumstances but can be considered antecedent to compulsions and intrusive thoughts that drive persistent, potentially maladaptive behavior. Whether compulsive-like and habit-like behaviors share neural substrates is still being determined. Here, we investigated mice bred to display inflexible reward-seeking behaviors that are insensitive to action consequences. We found that these mice demonstrate habitual response biases and compulsive-like grooming behavior that was reversible by fluoxetine and ketamine. They also suffer dendritic spine attrition on excitatory neurons in the orbitofrontal cortex (OFC). Nevertheless, synaptic melanocortin 4 receptor (MC4R), a factor implicated in compulsive behavior, is preserved, leading to the hypothesis that Mc4r+ OFC neurons may drive aberrant behaviors. Repeated chemogenetic stimulation of Mc4r+ OFC neurons triggered compulsive and not inflexible or habitual response biases in otherwise typical mice. Thus, Mc4r+ neurons within the OFC appear to drive compulsive-like behavior that is dissociable from habitual behavior. Understanding which neuron populations trigger distinct behaviors may advance efforts to mitigate harmful compulsions.

Histamine H3 receptor antagonism modulates autism-like hyperactivity but not repetitive behaviors in BTBR T+Itpr3tf/J inbred mice.

BACKGROUND: Autism spectrum disorders (ASDs) are a group of neurodevelopmental conditions defined by behavioral deficits in social communication and interactions, mental inflexibility and repetitive behaviors. Converging evidence from observational and preclinical studies suggest that excessive repetitive behaviors in people with ASD may be due to elevated histaminergic H3 receptor signaling in the striatum. We hypothesized that systemic administration of pharmacological histamine H3 receptor antagonists would attenuate the expression of repetitive behaviors in the BTBR T+Itpr3tf/J (BTBR) mouse inbred strain, an established mouse model presenting autism-like repetitive behaviors and novelty-induced hyperactivity. We further aimed to investigate whether agonism of the histamine H3 receptor would be sufficient to induce repetitive behaviors in the C57BL/6J control mouse strain. METHODS: Different doses of H3 receptor agonists (i.e., (R)-α-methylhistamine and immethridine) and H3 receptor antagonists/inverse agonists (i.e., ciproxifan and pitolisant) were administered via intraperitoneal (i.p.) injection in male mice to characterize the acute effects of these compounds on ASD-related behavioral readouts. RESULTS: The highly selective H3 receptor agonist immethridine significantly increased the time spent in stereotypic patterns in C57BL/6J mice, but this effect appeared to be driven by general sedative properties of the compound. High doses of pitolisant significantly decreased locomotor hyperactivity in novel environments in BTBR mice, without significant effects on repetitive behaviors. CONCLUSIONS: Based on our findings, we conclude that acute H3 receptor manipulation mainly affected general motor activity levels in novel environments. Small changes in stereotyped behaviors were observed but appeared to be driven by altered general activity levels.

Correlation among gut microbiota, fecal metabolites and autism-like behavior in an adolescent valproic acid-induced rat autism model.

This study aims to understand the relationship between fecal metabolites and gut microbiota in an adolescent valproic acid-induced rat autism model (VPA-exposed offspring). We analyzed the fecal samples of VPA-exposed offspring using 16S rRNA gene sequencing and untargeted metabolomics. Autism-like behavior was evaluated by a three-chamber sociability test and a self-grooming test. Based on these data, we analyzed the association among fecal metabolites, gut microbiota and autism-like behavior. Behavioral tests showed that VPA-exposed offspring displayed typical autism-like behavior. Forty-nine named differential fecal metabolites and 14 enriched KEGG pathways were identified between the VPA and control groups. Five fecal metabolites may be used as characteristic metabolites. The richness and diversity of gut microbiota did not differ between the two groups, while the overall composition of gut microbiota was significantly different. Candidatus_Saccharimonas, Desulfovibrio, [Eubacterium]_xylanophilum_group and Ruminococcus_2 were the characteristic genera of VPA-exposed offspring. Correlation analysis revealed a tight relationship among gut microbiota, fecal metabolites and autistic behavior in VPA-exposed offspring. This study illustrates that specific alterations in gut microbiota and fecal metabolites may be regarded as characteristics of VPA-exposed offspring. The characteristic gut microbiota and fecal metabolites as well as their relationship may play a crucial role in autism-like behavior caused by prenatal exposure to VPA.

Effects of the Partial M1 Muscarinic Cholinergic Receptor Agonist CDD-0102A on Stereotyped Motor Behaviors and Reversal Learning in the BTBR Mouse Model of Autism.

BACKGROUND: Autism spectrum disorders (ASD) are a set of neurodevelopmental disorders marked by a lack of social interaction, restrictive interests, and repetitive behaviors. There is a paucity of pharmacological treatments to reduce core ASD symptoms. Various lines of evidence indicate that reduced brain muscarinic cholinergic receptor activity may contribute to an ASD phenotype. METHODS: The present experiments examined whether the partial M1 muscarinic receptor agonist, 5-(3-ethyl-1,2,4-oxadiazol-5-yl)-1,4,5,6-tetrahydropyrimidine hydrochloride (CDD-0102A), alleviates behavioral flexibility deficits and/or stereotyped motor behaviors in the BTBR mouse model of autism. Behavioral flexibility was tested using a reversal learning test. Stereotyped motor behaviors were measured by eliciting digging behavior after removal of nesting material in a home cage and by measuring repetitive grooming. RESULTS: CDD-0102A (0.2 and 0.6 mg/kg but not 1.2 mg/kg) injected prior to reversal learning attenuated a deficit in BTBR mice but did not affect performance in B6 mice. Acute CDD-0102A treatment (1.2 and 3 mg/kg) reduced self-grooming in BTBR mice and reduced digging behavior in B6 and BTBR mice. The M1 muscarinic receptor antagonist VU0255035 (3 mg/kg) blocked the effect of CDD-0102A on grooming behavior. Chronic treatment with CDD-0102A (1.2 mg/kg) attenuated self-grooming and digging behavior in BTBR mice. Direct CDD-0102A infusions (1 µg) into the dorsal striatum reduced elevated digging behavior in BTBR mice. In contrast, CDD-0102A injections in the frontal cortex were not effective. CONCLUSIONS: The results suggest that treatment with a partial M1 muscarinic receptor agonist may reduce repetitive behaviors and restricted interests in autism in part by stimulating striatal M1 muscarinic receptors.

Muscarinic regulation of self-grooming behavior and ultrasonic vocalizations in the context of open-field habituation in rats.

Laboratory rats repeatedly exposed to an open field (OF) apparatus display increasingly high levels of grooming -especially that characterized by long and complex sequences- which has been taken as an additional index of novelty habituation. We hypothesized that disrupting such a learning process by administering an amnesic drug as the antimuscarinic scopolamine (SCP) could delay the appearance of more complex grooming subtypes. Thus, rats were pretreated either with SCP (15 mg/kg or 30 mg/kg) or vehicle (VEH) upon four one-day apart OF (OF1-4). On a fifth assessment, all rats received VEH to analyze the likely carry-over effect of SCP. Finally, we measured 50-kHz and 22-kHz ultrasonic vocalizations (USVs) as reliable markers of positive and negative emotionality, respectively. We found that SCP increased locomotion during OF1 and reduced rearing on OF1-OF4, causing no disruption in habituation over tests. SCP prevented the increase of total grooming time by inhibiting complex grooming subtypes and promoting short cephalic sequences. Despite the SCP-induced alterations on grooming agreed with our hypotheses, those changes may have resulted from a motor impairment that could have also affected rearing behavior. Additionally, SCP suppressed 50-kHz USVs while marginally increased 22-kHz calls. Once SCP was withdrawn, rearing, grooming, and some 50-kHz USVs subtypes returned to VEH levels, suggesting that novelty habituation occurred despite the SCP administration. Altogether, that mixed profile of SCP-induced behavioral changes may derive from the complex interplay between the contrasting action of SCP on different brain regions and the doses here used.

Improvement effects of tanshinone on the impaired cognition and motor function in MCAO mice with ischemic penumbra.

This study aims to investigate the effects of tanshinone on improving the impaired cognition and motor function in MCAO model mice with ischemic penumbra. MWM test was carried out to evaluate the spatial learning and memory performance and the cognitive function of mice. The area of cerebral infarction was analyzed by immunohistochemistry. The TUNEL apoptosis detection kit was used to detect neuronal apoptosis. On the 25th day, the induction model group had lower body weight than the control group and the tanshinone treatment group; the induction model group had decreased walking deficiency and correct area escape times than the other two groups; while, tanshinone treatment group had higher movement distance, movement speed, periphery entry frequency, grooming rate, decreased center entry frequency, infarction area, apoptotic neuron number, latent escape time than induction model group; additionally, the control group had increased periphery and corner entry frequency, but decreased center entry frequency and latent escape time than the other two groups. Tanshinone can reduce neuronal damage in the ischemic penumbra after stroke, improve the integrity of white and gray matter, and restore connectivity in motor and cognitive functions, thereby supporting recovery from ischemic stroke.

LSD-stimulated behaviors in mice require ß-arrestin 2 but not ß-arrestin 1.

Recent evidence suggests that psychedelic drugs can exert beneficial effects on anxiety, depression, and ethanol and nicotine abuse in humans. However, their hallucinogenic side-effects often preclude their clinical use. Lysergic acid diethylamide (LSD) is a prototypical hallucinogen and its psychedelic actions are exerted through the 5-HT2A serotonin receptor (5-HT2AR). 5-HT2AR activation stimulates Gq- and ß-arrestin- (ßArr) mediated signaling. To separate these signaling modalities, we have used ßArr1 and ßArr2 mice. We find that LSD stimulates motor activities to similar extents in WT and ßArr1-KO mice, without effects in ßArr2-KOs. LSD robustly stimulates many surrogates of psychedelic drug actions including head twitches, grooming, retrograde walking, and nose-poking in WT and ßArr1-KO animals. By contrast, in ßArr2-KO mice head twitch responses are low with LSD and this psychedelic is without effects on other surrogates. The 5-HT2AR antagonist MDL100907 (MDL) blocks the LSD effects. LSD also disrupts prepulse inhibition (PPI) in WT and ßArr1-KOs, but not in ßArr2-KOs. MDL restores LSD-mediated disruption of PPI in WT mice; haloperidol is required for normalization of PPI in ßArr1-KOs. Collectively, these results reveal that LSD's psychedelic drug-like actions appear to require ßArr2.

Discovery of G Protein-Biased Antagonists against 5-HT7R.

5-HT7R belongs to a family of G protein-coupled receptors and is associated with a variety of physiological processes in the central nervous system via the activation of the neurotransmitter serotonin (5-HT). To develop selective and biased 5-HT7R ligands, we designed and synthesized a series of pyrazolyl-diazepanes 2 and pyrazolyl-piperazines 3, which were evaluated for binding affinities to 5-HTR subtypes and functional selectivity for G protein and ß-arrestin signaling pathways of 5-HT7R. Among them, 1-(3-(3-chlorophenyl)-1H-pyrazol-4-yl)-1,4-diazepane 2c showed the best binding affinity for 5-HT7R and selectivity over other 5-HTR subtypes. It was also revealed as a G protein-biased antagonist. The self-grooming behavior test was performed with 2c in vivo with Shank3-/- transgenic (TG) mice, wherein 2c significantly reduced self-grooming duration time to the level of wild-type mice. The results suggest that 5-HT7R could be a potential therapeutic target for treating autism spectrum disorder stereotypy.

Blocking NK1 receptors disrupts the sequential and temporal organization of chain grooming in rats.

The basal ganglia are a group of sub-cortical structures believed to play a critical role in action selection and sequencing. The striatum is the largest input structure of the basal ganglia and contains the neuropeptide substance P in abundance. Recent computational work has suggested that substance P could play a critical role in action sequence performance and acquisition, but this has not been tested experimentally before. The aim of the present study was to test how blocking substance P's main NK1-type receptors affected the sequential and temporal organization of spontaneous behavioral patterns. We did this in rats by focusing on the grooming chain, an innate and highly stereotyped ordered sequence. We performed an open field experiment in which the NK1 receptor antagonist L-733,060 was injected intraperitoneally in rats at two doses (2 and 4 mg/kg/ml), in a within-subject counterbalanced design. We used first order transition probabilities, Variable Length Markov Models, entropy metrics and T-pattern analysis to evaluate the effects of L-733,060 on sequential and temporal aspects of spontaneously ordered behavioral sequences. Our results suggest that blocking NK1 receptors made the transitions between the grooming chain elements significantly more variable, the transition structure of the grooming bouts simpler, and it increased the probability of transitioning from active to inactive states. Overall, this suggest that blocking substance P receptors led to a general break down in the fluency of spontaneous behavioral sequences, suggesting that substance P could be playing a key role in the implementation of sequential patterns.

Protective effects of L-carnitine on behavioral alterations and neuroinflammation in striatum of glutaryl-COA dehydrogenase deficient mice.

Glutaric acidemia type 1 (GA1) is caused by glutaryl-CoA dehydrogenase deficiency that leads to a blockage in the metabolic route of the amino acids lysine and tryptophan and subsequent accumulation of glutaric acid (GA), 3-hydroxyglutaric acids and glutarylcarnitine (C5DC). Patients predominantly manifest neurological symptoms, associated with acute striatal degeneration, as well as progressive cortical and striatum injury whose pathogenesis is not yet fully established. Current treatment includes protein/lysine restriction and l-carnitine supplementation of (L-car). The aim of this work was to evaluate behavior parameters and pro-inflammatory factors (cytokines IL-1ß, TNF-α and cathepsin-D levels), as well as the anti-inflammatory cytokine IL10 in striatum of knockout mice (Gcdh-/-) and wild type (WT) mice submitted to a normal or a high Lys diet. The potential protective effects of L-car treatment on these parameters were also evaluated. Gcdh-/- mice showed behavioral changes, including lower motor activity (decreased number of crossings) and exploratory activity (reduced number of rearings). Also, Gcdh-/- mice had significantly higher concentrations of glutarylcarnitine (C5DC) in blood and cathepsin-D (CATD), interleukin IL-1ß and tumor factor necrosis alpha (TNF-α) in striatum than WT mice. Noteworthy, L-car treatment prevented most behavioral alterations, normalized CATD levels and attenuated IL-1ß levels in striatum of Gcdh-/- mice. Finally, IL-1ß was positively correlated with CATD and C5DC levels and L-car was negatively correlated with CATD. Our results demonstrate behavioral changes and a pro-inflammatory status in striatum of the animal model of GA1 and, most importantly, L-car showed important protective effects on these alterations.

Profile of a short-acting κ-antagonist, LY2795050, on self-grooming behaviors, forced swim test and locomotor activity: sex comparison in mice.

BACKGROUND: Novel short-acting κ(kappa)-opioid receptor selective antagonists are translational tools to examine the impact of the κ-receptor/dynorphin system in assays related to central nervous system dysfunction (e.g., substance use disorders, anhedonia and depression). The effects of such compounds have been compared in males and females under very limited conditions. AIMS: The goal of this study was to examine potential sex differences in the effects of a κ-agonist and a short-acting κ-antagonist in an ethologically relevant test of anhedonia, the "splash test" of self-grooming, and also in the forced swim test and in locomotor activity. METHODS: We examined the dose-dependence of grooming deficits caused by the κ-agonist U50,488 (0.1-3.2 mg/kg intraperitoneal (i.p.)) in gonadally intact adult male and female C57BL/6J mice. We then compared the effects of the short-acting κ-antagonist LY2795050 ((3-chloro-4-(4-(((2S)-2-pyridin-3-ylpyrrolidin-1-yl)methyl) phenoxy)benzamide)); 0.032-0.1 mg/kg i.p.) in blocking grooming deficits caused by U50,488 (3.2 mg/kg). The effects of LY2795050 were also studied in the forced swim test (FST). The effects of LY2795050 in blocking the locomotor depressant effects of U50,488 (10 mg/kg) were also studied. RESULTS: U50,488 produced dose-dependent grooming deficits in male and female mice, and LY2795050 prevented these effects. In contrast, LY2795050 decreased immobility in the FST in males at a dose of 0.1 mg/kg, but not in females, up to a dose of 0.32 mg/kg. Also, LY2795050 (0.32 mg/kg) prevented and also reversed the locomotor-depressant effects of U50,488 (10 mg/kg), in males and females. CONCLUSIONS: This study further implicates the κ-receptor system in ethologically relevant aspects of anhedonia, and confirms sexual dimorphism in some behavioral effects of novel κ-antagonists.

Sodium phenylbutyrate reduces repetitive self-grooming behavior and rescues social and cognitive deficits in mouse models of autism.

Autism spectrum disorder (ASD) is a neurodevelopment disorder characterized by deficits in social interaction and restrictive, repetitive, and stereotypical patterns of behavior. However, there is no pharmacological drug that is currently used to target these core ASD symptoms. Sodium phenylbutyrate (NaPB) is a well-known long-term treatment of urea cycle disorders in children. In this study, we assessed the therapeutic effects of NaPB, which is a chemical chaperone as well as histone deacetylase inhibitor on a BTBR T + Itpr3tf/J (BTBR) mice model of ASD. We found that acute and chronic treatment of NaPB remarkably improved, not only core ASD symptoms, including repetitive behaviors and sociability deficit, but also cognitive impairment in the BTBR mice. NaPB substantially induced histone acetylation in the brain of the BTBR mice. Intriguingly, the therapeutic effects of NaPB on autistic-like behaviors, such as repetitive behaviors, impaired sociability, and cognitive deficit also showed in the valproic acid (VPA)-induced mouse model of autism. In addition, pentylenetetrazole (PTZ)-induced seizure was significantly attenuated by NaPB treatment in C57BL/6J and BTBR mice. These findings suggest that NaPB may provide a novel therapeutic approach for the treatment of patients with ASD.

The Multi-Targeting Ligand ST-2223 with Histamine H3 Receptor and Dopamine D2/D3 Receptor Antagonist Properties Mitigates Autism-Like Repetitive Behaviors and Brain Oxidative Stress in Mice.

Autism spectrum disorder (ASD) is a complex heterogeneous neurodevelopmental disorder characterized by social and communicative impairments, as well as repetitive and restricted behaviors (RRBs). With the limited effectiveness of current pharmacotherapies in treating repetitive behaviors, the present study determined the effects of acute systemic treatment of the novel multi-targeting ligand ST-2223, with incorporated histamine H3 receptor (H3R) and dopamine D2/D3 receptor affinity properties, on ASD-related RRBs in a male Black and Tan BRachyury (BTBR) mouse model of ASD. ST-2223 (2.5, 5, and 10 mg/kg, i.p.) significantly mitigated the increase in marble burying and self-grooming, and improved reduced spontaneous alternation in BTBR mice (all p < 0.05). Similarly, reference drugs memantine (MEM, 5 mg/kg, i.p.) and aripiprazole (ARP, 1 mg/kg, i.p.), reversed abnormally high levels of several RRBs in BTBR (p < 0.05). Moreover, ST-2223 palliated the disturbed anxiety levels observed in an open field test (all p < 0.05), but did not restore the hyperactivity parameters, whereas MEM failed to restore mouse anxiety and hyperactivity. In addition, ST-2223 (5 mg/kg, i.p.) mitigated oxidative stress status by decreasing the elevated levels of malondialdehyde (MDA), and increasing the levels of decreased glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT) in different brain parts of treated BTBR mice (all p < 0.05). These preliminary in vivo findings demonstrate the ameliorative effects of ST-2223 on RRBs in a mouse model of ASD, suggesting its pharmacological prospective to rescue core ASD-related behaviors. Further confirmatory investigations on its effects on various brain neurotransmitters, e.g., dopamine and histamine, in different brain regions are still warranted to corroborate and expand these initial data.

Aggravation of autism-like behavior in BTBR T+tf/J mice by environmental pollutant, di-(2-ethylhexyl) phthalate: Role of nuclear factor erythroid 2-related factor 2 and oxidative enzymes in innate immune cells and cerebellum.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder which manifests itself in early childhood and is distinguished by recurring behavioral patterns, and dysfunction in social/communication skills. Ubiquitous environmental pollutant, di-2-ethylhexyl phthalate (DEHP) is one of the most frequently used plasticizers in various industrial products, e.g. vinyl flooring, plastic toys, and medical appliances. DEHP gets easily released into the environment and leads to human exposure through various routes. DEHP has been described to be linked with oxidative stress in various organs in animal/human studies. Increased concentration of DEHP has also been detected in ASD children which indicates an association between phthalates exposure and ASD. However, effect of DEHP on autism-like behavior has not been investigated previously. Therefore, this study probed the effect of DEHP on autism-like behavior (marble burying, self-grooming and sociability) and innate immune cells (dendritic cells/neutrophils)/cerebellar oxidant-antioxidant balance (NFkB, iNOS, NADPH oxidase, nitrotyrosine, lipid peroxides, Nrf2, SOD, GPx) in BTBR and C57 mice. Our data show that DEHP treatment causes worsening of autism-like behavior in BTBR mice which is associated with enhancement of oxidative stress in innate immune cells and cerebellum with concomitant lack of antioxidant protection. DEHP also causes oxidative stress in C57 mice in both innate immune cells and cerebellar compartment, however there is Nrf2-mediated induction of enzymatic antioxidants which protects them from upregulated oxidative stress. This proposes the notion that ubiquitous environmental pollutants such as DEHP may be involved in the pathogenesis/progression of ASD through dysregulation of antioxidant-antioxidant balance in innate immune cells and cerebellum.

Serotonin 6 receptor blockade reduces repetitive behavior in the BTBR mouse model of autism spectrum disorder.

Autism spectrum disorder (ASD) is characterized by the expression of restricted repetitive behaviors (RRBs) and impairments in social recognition and communication. Previous studies have found that specific serotonin (5-HT) receptor modulation can attenuate repetitive behaviors expressed in specific mouse strains. The present study examined how 5-HT6 receptor blockade impacts the expression of repetitive behaviors in two different mouse strains that demonstrate elevated restricted, repetitive behavior and impairments in social behavior. BTBR T+ Itpr3tf /J (BTBR), C58/J (C58) and control C57BL/6J strains were behaviorally tested after acute treatment with the 5-HT6 receptor antagonist BGC 20-761 (BGC) or vehicle. BTBR mice express high levels of self-grooming behavior while C58 mice display high rates of repetitive jumping behavior. Similarly, the effect of 5-HT6 receptor blockade was also tested on social approach behaviors in both strains. BGC significantly reduced repetitive grooming in both female and male BTBR mice compared to vehicle-treated BTBR mice. BGC treatment did not attenuate social approach impairments in either female or male BTBR mice compared to vehicle-treated BTBR mice. Follow-up dose response studies were conducted on repetitive grooming and locomotor activity in BTBR mice. All doses reduced repetitive grooming in female and male BTBR mice. Acute treatment with BGC only reduced locomotor activity with the lower doses. In C58 mice, BGC treatment did not significantly attenuate flipping or general social approach behaviors. Instead, BGC significantly increased social sniff time in female C58 mice. While 5-HT6 receptor blockade did not attenuate the social impairments found in BTBR mice, this treatment did increase sniff time in female C58 mice. Although the lower doses of BGC deduced locomotion, the higher dose attenuated repetitive grooming in BTBR mice while sparing locomotor activity. Together these findings suggest the therapeutic effects of 5-HT6 receptor blockade are complex and may be specific to the types of repetitive behaviors expressed.

Exposure to bisphenol A differentially impacts neurodevelopment and behavior in Drosophila melanogaster from distinct genetic backgrounds.

Bisphenol A (BPA) is a ubiquitous environmental chemical that has been linked to behavioral differences in children and shown to impact critical neurodevelopmental processes in animal models. Though data is emerging, we still have an incomplete picture of how BPA disrupts neurodevelopment; in particular, how its impacts may vary across different genetic backgrounds. Given the genetic tractability of Drosophila melanogaster, they present a valuable model to address this question. Fruit flies are increasingly being used for assessment of neurotoxicants because of their relatively simple brain structure and variety of measurable behaviors. Here we investigated the neurodevelopmental impacts of BPA across two genetic strains of Drosophila-w1118 (control) and the Fragile X Syndrome (FXS) model-by examining both behavioral and neuronal phenotypes. We show that BPA induces hyperactivity in larvae, increases repetitive grooming behavior in adults, reduces courtship behavior, impairs axon guidance in the mushroom body, and disrupts neural stem cell development in the w1118 genetic strain. Remarkably, for every behavioral and neuronal phenotype examined, the impact of BPA in FXS flies was either insignificant or contrasted with the phenotypes observed in the w1118 strain. This data indicates that the neurodevelopmental impacts of BPA can vary widely depending on genetic background and suggests BPA may elicit a gene-environment interaction with Drosophila fragile X mental retardation 1 (dFmr1)-the ortholog of human FMR1, which causes Fragile X Syndrome and is associated with autism spectrum disorder.

The Role of Nicotinic Receptors in the Attenuation of Autism-Related Behaviors in a Murine BTBR T + tf/J Autistic Model.

Nicotinic receptors are distributed throughout the central and peripheral nervous system. Postmortem studies have reported that some nicotinic receptor subtypes are altered in the brains of autistic people. Recent studies have demonstrated the importance of nicotinic acetylcholine receptors (nAChRs) in the autistic behavior of BTBR T + tf/J mouse model of autism. This study was undertaken to examine the behavioral effects of targeted nAChRs using pharmacological ligands, including nicotine and mecamylamine in BTBR T + tf/J and C57BL/6J mice in a panel of behavioral tests relating to autism. These behavioral tests included the three-chamber social interaction, self-grooming, marble burying, locomotor activity, and rotarod test. We examined the effect of various oral doses of nicotine (50, 100, and 400 mcg/mL; po) over a period of 2 weeks in BTBR T + tf/J mouse model. The results indicated that the chronic administration of nicotine modulated sociability and repetitive behavior in BTBR T + tf/J mice while no effects observed in C57BL/6J mice. Furthermore, the nonselective nAChR antagonist, mecamylamine, reversed nicotine effects on sociability and increased repetitive behaviors in BTBR T + tf/J mice. Overall, the findings indicate that the pharmacological modulation of nicotinic receptors is involved in modulating core behavioral phenotypes in the BTBR T + tf/J mouse model. LAY SUMMARY: The involvement of brain nicotinic neurotransmission system plays a crucial role in regulating autism-related behavioral features. In addition, the brain of the autistic-like mouse model has a low acetylcholine level. Here, we report that nicotine, at certain doses, improved sociability and reduced repetitive behaviors in a mouse model of autism, implicating the potential therapeutic values of a pharmacological intervention targeting nicotinic receptors for autism therapy. Autism Res 2020, 13: 1311-1334. © 2020 International Society for Autism Research, Wiley Periodicals, Inc.

Tandospirone, a Partial 5-HT1A Receptor Agonist, Administered Systemically or Into Anterior Cingulate Attenuates Repetitive Behaviors in Shank3B Mice.

BACKGROUND: Several cases of autism spectrum disorder have been linked to mutations in the SHANK3 gene. Haploinsufficiency of the SHANK3 gene contributes to Phelan-McDermid syndrome, which often presents an autism spectrum disorder phenotype along with moderate to severe intellectual disability. A SHANK3 gene deletion in mice results in elevated excitation of cortical pyramidal neurons that alters signaling to other brain areas. Serotonin 1A receptors are highly expressed on layer 2 cortical neurons and are known to have inhibitory actions. Serotonin 1A receptor agonist treatment in autistic cases with SHANK3 mutations and possibly other cases may restore excitatory and inhibitory balance that attenuates core symptoms. METHODS: A series of experiments investigated the effects of acute tandospirone treatment on spatial learning and self-grooming, subchronic treatment of tandospirone on self-grooming behavior, and the effect of tandospirone infusion into the anterior cingulate on self-grooming behavior. RESULTS: Only male Shank3B+/- mice exhibited a spatial learning deficit and elevated self-grooming. Acute i.p. injection of tandospirone, 0.01 and 0.06 mg/kg in male Shank3B+/- mice, attenuated a spatial acquisition deficit by improving sensitivity to positive reinforcement and reduced elevated self-grooming behavior. Repeated tandospirone (0.06 mg/kg) treatment attenuated elevated self-grooming behavior in male Shank3B+/- mice. Tandospirone injected into the anterior cingulate/premotor area reduced self-grooming behavior in male Shank3B+/- mice. CONCLUSIONS: These results suggest that stimulation of cortical serotonin 1A receptors may reduce repetitive behaviors and cognitive impairments as observed in autism spectrum disorder, possibly by attenuating an excitation/inhibition imbalance. Further, tandospirone may serve as a treatment in autism spectrum disorder and other disorders associated with SHANK3 mutations.

Divergent pathways mediate 5-HT1A receptor agonist effects on close social interaction, grooming and aggressive behaviour in mice: Exploring the involvement of the oxytocin and vasopressin systems.

BACKGROUND: 5-HT1A receptor (5-HT1AR) abnormalities are implicated in aggression, and there has been considerable interest in developing 5-HT1AR agonists for treating aggression. Endogenous oxytocin (OXT) released upon stimulation of 5-HT1ARs in the hypothalamus mediates at least some of the effects of 5-HT1AR agonists on social behaviour. AIMS: Given 5-HT1AR, OXT receptor (OXTR) and vasopressin V1a receptor (V1aR) agonists can all reduce aggression, the current study aimed to determine whether the anti-aggressive effects of 5-HT1AR stimulation can also be explained by downstream actions at OXTRs and/or V1aRs in a mouse model of non-territorial, hyper-aggressive behaviour. METHODS: Male Swiss mice (N=80) were socially isolated or group housed for six weeks prior to the start of testing. Testing involved placing two unfamiliar weight- and condition-matched mice together in a neutral context for 10 minutes. RESULTS: Social isolation led to a pronounced increase in aggressive behaviour, which was dose-dependently inhibited by the 5-HT1AR agonist 8-OH-DPAT (0.1, 0.3 and 1 mg/kg intraperitoneally (i.p.)), with accompanying increases in close social contact (huddling) and grooming. The effects of 8-OH-DPAT on aggression, huddling and grooming were blocked by pretreatment with a selective 5-HT1AR antagonist (WAY-100635; 0.1 mg/kg i.p.). The anti-aggressive effects of 8-OH-DPAT were unaffected by an OXTR antagonist (L-368,899; 10 mg/kg i.p.), whereas the effects on huddling and grooming were inhibited. Pretreatment with a V1aR antagonist (SR49059; 20 mg/kg i.p.) had no effect. CONCLUSIONS: Our study suggests that stimulation of endogenous oxytocin is involved in the effects of 5-HT1AR activation on close social contact and grooming but not aggression.

Autism-Associated Shank3 Is Essential for Homeostatic Compensation in Rodent V1.

Mutations in Shank3 are strongly associated with autism spectrum disorders and neural circuit changes in several brain areas, but the cellular mechanisms that underlie these defects are not understood. Homeostatic forms of plasticity allow central circuits to maintain stable function during experience-dependent development, leading us to ask whether loss of Shank3 might impair homeostatic plasticity and circuit-level compensation to perturbations. We found that Shank3 loss in vitro abolished synaptic scaling and intrinsic homeostatic plasticity, deficits that could be rescued by treatment with lithium. Further, Shank3 knockout severely compromised the in vivo ability of visual cortical circuits to recover from perturbations to sensory drive. Finally, lithium treatment ameliorated a repetitive self-grooming phenotype in Shank3 knockout mice. These findings demonstrate that Shank3 loss severely impairs the ability of central circuits to harness homeostatic mechanisms to compensate for perturbations in drive, which, in turn, may render them more vulnerable to such perturbations.