Sex-biasing influence of autism-associated Ube3a gene overdosage at connectomic, behavioral, and transcriptomic levels.

Genomic mechanisms enhancing risk in males may contribute to sex bias in autism. The ubiquitin protein ligase E3A gene (Ube3a) affects cellular homeostasis via control of protein turnover and by acting as transcriptional coactivator with steroid hormone receptors. Overdosage of Ube3a via duplication or triplication of chromosomal region 15q11-13 causes 1 to 2% of autistic cases. Here, we test the hypothesis that increased dosage of Ube3a may influence autism-relevant phenotypes in a sex-biased manner. We show that mice with extra copies of Ube3a exhibit sex-biasing effects on brain connectomics and autism-relevant behaviors. These effects are associated with transcriptional dysregulation of autism-associated genes, as well as genes differentially expressed in 15q duplication and in autistic people. Increased Ube3a dosage also affects expression of genes on the X chromosome, genes influenced by sex steroid hormone, and genes sex-differentially regulated by transcription factors. These results suggest that Ube3a overdosage can contribute to sex bias in neurodevelopmental conditions via influence on sex-differential mechanisms.

The role of interoceptive awareness in shaping the relationship between desire thinking and cigarette consumption.

Interoception, the ability to sense and interpret bodily sensations, has recently emerged as a crucial factor in substance use disorders, including smoking. However, the role of interoceptive awareness in tobacco use remains poorly understood. The relationship between interoceptive ability and addictive behavior is complex, and attempting to conceptualize it as a linear association is unlikely to fully capture the complexity of the mechanisms underlying cravings and urges. We hypothesized that the role played by interoceptive awareness in tobacco use is deeply linked to desire thinking, that is, the conscious and voluntary cognitive process orienting to prefigure images, information, and memories about positive target-related experiences. Desire thinking is typically observed in addiction, where it may contribute to interpreting specific bodily sensations, such as the perceived need for a cigarette. From this perspective, the physiological impact and inclination toward desire thinking contribute to a higher daily cigarette consumption, particularly in situations of low interoceptive awareness. To test this hypothesis, we assessed the physiological activation, the tendency toward desire thinking about smoking, cigarette consumption, and the interoceptive abilities of smoking volunteers. Through a moderation analysis, we showed that desire thinking about smoking predicts a higher number of cigarettes per day in individuals with lower interoceptive awareness (p < .05). These findings suggest that the relationship between desire thinking and interoceptive awareness is a fundamental component of tobacco use, highlighting the importance of taking into account the bodily feedback deriving from the cognitive representation of smoking in addiction research and therapy.

Alterations of Perineuronal Net Expression and Abnormal Social Behavior and Whisker-dependent Texture Discrimination in Mice Lacking the Autism Candidate Gene Engrailed 2.

GABAergic interneurons and perineuronal nets (PNNs) are important regulators of plasticity throughout life and their dysfunction has been implicated in the pathogenesis of several neuropsychiatric conditions, including autism spectrum disorders (ASD). PNNs are condensed portions of the extracellular matrix (ECM) that are crucial for neural development and proper formation of synaptic connections. We previously showed a reduced expression of GABAergic interneuron markers in the hippocampus and somatosensory cortex of adult mice lacking the Engrailed2 gene (En2-/- mice), a mouse model of ASD. Since alterations in PNNs have been proposed as a possible pathogenic mechanism in ASD, we hypothesized that the PNN dysfunction may contribute to the neural and behavioral abnormalities of En2-/- mice. Here, we show an increase in the PNN fluorescence intensity, evaluated by Wisteria floribunda agglutinin, in brain regions involved in social behavior and somatosensory processing. In addition, we found that En2-/- mice exhibit altered texture discrimination through whiskers and display a marked decrease in the preference for social novelty. Our results raise the possibility that altered expression of PNNs, together with defects of GABAergic interneurons, might contribute to the pathogenesis of social and sensory behavioral abnormalities.

The relationship between perseverative thinking, proactive control, and inhibition in psychological distress: a study in a women's cohort.

Cognitive control is a core feature of several mental disorders. A recent account poses that health problems may derive from proactive forms of cognitive control that maintain stress representation over time. The working hypothesis of the present study is that psychological distress is caused by the tendency to select a particular maladaptive self-regulation strategy over time, namely perseverative thinking, rather than by transient stimulus-response patterns. To test this hypothesis, we asked 84 women to carry out a battery of standardized questionnaires regarding their tendency to undertake perseverative thinking and their level of psychological distress, followed by cognitive tasks measuring the tendency to use proactive versus reactive control modality and disinhibition. Through a series of mediation analyses, we demonstrate that the tendency to use proactive control correlates with psychological distress and that this relation is mediated by perseverative thinking. Moreover, we show that the relation between low inhibitory control and psychological stress is more strongly mediated by perseverative thinking than impulsiveness, a classical construct that focuses on more transient reactions to stimuli. The present results underline the importance of considering psychological distress as the consequence of a maladaptive way of applying control over time, rather than the result of a general deficit in cognitive control abilities.

Twisted memories: Addiction-related engrams are strengthened by desire thinking.

Associative learning plays a central role in addiction by reinforcing associations between environmental cues and addiction-related information. Unsupervised learning models posit that memories are adjusted based on how strongly these representations are coactivated during the retrieval process. From a different perspective, clinical models of addiction posit that the escalation and persistence of craving may depend on desire thinking, a thinking style orienting to prefigure information about positive addiction-related experiences. In the present work, we tested the main hypothesis that desire thinking is a key factor in the strengthening of addiction-related associations. A group of adult smoking volunteers (N = 26) engaged in a period of desire thinking before performing an associative learning task in which neutral words (cues) were shown along with images (smoking-related vs. neutral context) at different frequencies. Two retrieval tests were administered, one immediately after encoding and the other after 24 h, to test how the recall of associations changed as a function of retention interval. Two control groups, smokers (N = 21) and non-smokers (N = 22), performed a similar procedure, with a neutral imagination task replacing desire thinking. Participants who engaged in desire thinking increased their performance from the first to the second retrieval test only for the most frequent smoking-related associations. Crucially, this selective effect was not observed in the two control groups. These results provide behavioral evidence in support of the idea that desire thinking plays a role in strengthening addiction-related associations. Thus, this thinking process may be considered a target for reconsolidation-based conceptualizations of, and treatments for, addiction.

Neural bases of loss aversion when choosing for oneself versus known or unknown others.

Despite the ubiquitous interdependence between one's own decisions and others' welfare, and the controversial evidence on the behavioral effect of choosing for others, the neural bases of making decisions for another versus oneself remain unexplored. We investigated whether loss aversion (LA; the tendency to avoid losses over approaching equivalent gains) is modulated by (i) choosing for oneself, other individuals, or both; (ii) knowing or not knowing the other recipients; or (iii) an interaction between these factors. We used fMRI to assess the brain activations associated with choosing whether to accept or reject mixed gambles, either for oneself, for another player, or both, in 2 groups of 28 participants who had or had not briefly interacted with the other players before scanning. Participants displayed higher LA for choices involving their payoff compared with those affecting only the payoff of other, known, players. This "social" modulation of decision-making was found to engage the dorsomedial prefrontal cortex and its inhibitory connectivity to the middle cingulate cortex. This pattern might underpin decision-making for known others via self-other distinction processes associated with dorsomedial prefrontal areas, with this in turn promoting the inhibition of socially oriented responses through the downregulation of the midcingulate node of the empathy network.

Chronic social stress disrupts the intracellular redistribution of brain hexokinase 3 induced by shifts in peripheral glucose levels.

Chronic stress has the potential to impair health and may increase the vulnerability for psychiatric disorders. Emerging evidence suggests that specific neurometabolic dysfunctions play a role herein. In mice, chronic social defeat (CSD) stress reduces cerebral glucose uptake despite hyperglycemia. We hypothesized that this metabolic decoupling would be reflected by changes in contact sites between mitochondria and the endoplasmic reticulum, important intracellular nutrient sensors, and signaling hubs. We thus analyzed the proteome of their biochemical counterparts, mitochondria-associated membranes (MAMs) from whole brain tissue obtained from CSD and control mice. This revealed a lack of the glucose-metabolizing enzyme hexokinase 3 (HK3) in MAMs from CSD mice. In controls, HK3 protein abundance in MAMs and also in striatal synaptosomes correlated positively with peripheral blood glucose levels, but this connection was lost in CSD. We conclude that the ability of HK3 to traffic to sites of need, such as MAMs or synapses, is abolished upon CSD and surmise that this contributes to a cellular dysfunction instigated by chronic stress. KEY MESSAGES : Chronic social defeat (CSD) alters brain glucose metabolism CSD depletes hexokinase 3 (HK3) from mitochondria-associated membranes (MAMs) CSD results in loss of positive correlation between blood glucose and HK3 in MAMs and synaptosomes.

ATM rules neurodevelopment and glutamatergic transmission in the hippocampus but not in the cortex.

Interest in the function of ataxia-telangiectasia-mutated protein (ATM) is extensively growing as evidenced by preclinical studies that continuously link ATM with new intracellular pathways. Here, we exploited Atm+/- and Atm-/- mice and demonstrate that cognitive defects are rescued by the delivery of the antidepressant Fluoxetine (Fluox). Fluox increases levels of the chloride intruder NKCC1 exclusively at hippocampal level suggesting an ATM context-specificity. A deeper investigation of synaptic composition unveils increased Gluk-1 and Gluk-5 subunit-containing kainate receptors (KARs) levels in the hippocampus, but not in the cortex, of Atm+/- and Atm-/- mice. Analysis of postsynaptic fractions and confocal studies indicates that KARs are presynaptic while in vitro and ex vivo electrophysiology that are fully active. These changes are (i) linked to KCC2 activity, as the KCC2 blockade in Atm+/- developing neurons results in reduced KARs levels and (ii) developmental regulated. Indeed, the pharmacological inhibition of ATM kinase in adults produces different changes as identified by RNA-seq investigation. Our data display how ATM affects both inhibitory and excitatory neurotransmission, extending its role to a variety of neurological and psychiatric disorders.

Abnormal Whisker-Dependent Behaviors and Altered Cortico-Hippocampal Connectivity in Shank3b-/- Mice.

Abnormal tactile response is an integral feature of Autism Spectrum Disorders (ASDs), and hypo-responsiveness to tactile stimuli is often associated with the severity of ASDs core symptoms. Patients with Phelan-McDermid syndrome (PMS), caused by mutations in the SHANK3 gene, show ASD-like symptoms associated with aberrant tactile responses. The neural underpinnings of these abnormalities are still poorly understood. Here we investigated, in Shank3b-/- adult mice, the neural substrates of whisker-guided behaviors, a key component of rodents' interaction with the surrounding environment. We assessed whisker-dependent behaviors in Shank3b-/- adult mice and age-matched controls, using the textured novel object recognition (tNORT) and whisker nuisance (WN) test. Shank3b-/- mice showed deficits in whisker-dependent texture discrimination in tNORT and behavioral hypo-responsiveness to repetitive whisker stimulation in WN. Sensory hypo-responsiveness was accompanied by a significantly reduced activation of the primary somatosensory cortex (S1) and hippocampus, as measured by c-fos mRNA induction, a proxy of neuronal activity following whisker stimulation. Moreover, resting-state fMRI showed a significantly reduced S1-hippocampal connectivity in Shank3b mutants, in the absence of altered connectivity between S1 and other somatosensory areas. Impaired crosstalk between hippocampus and S1 might underlie Shank3b-/- hypo-reactivity to whisker-dependent cues, highlighting a potentially generalizable somatosensory dysfunction in ASD.