Metabolic, neuroendocrine and behavioral effects of social defeat in male and female mice using the chronic non-discriminatory social defeat stress model.

Stress-related disorders predominately affect females, yet preclinical models of chronic stress exclusively use males especially in models where social stressors are studied. Here, we implemented a 21-day novel social defeat paradigm in which a female and male C57 intruder are simultaneously placed in the cage of a territorial, resident CD-1 male mouse, and the resident proceeds to attack both intruders. Mice were given access to a regular laboratory diet, high in carbohydrates, and a palatable diet, high in fat. Chronic social defeat stress using this paradigm resulted in increased caloric intake in male and female mice, with the effects being more pronounced in females. We observed sex differences in high fat diet intake in response to stress, which was correlated with higher levels of plasma ghrelin observed in female mice but not male mice. Furthermore, females exposed to chronic stress displayed changes in growth hormone secretatogue receptor (ghsr) and neuropeptide-y (npy) expression in the arcuate nucleus of the hypothalamus, potentially increasing ghrelin sensitivity and inducing changes in diet choice and caloric intake. Behavioral results show that females tended to spend more time interacting during the social interaction test, compared to males who displayed higher vigilance towards the stranger mouse. Overall, our results highlight unique neurometabolic alterations in female mice in response to stress that is not present in male mice and may be important for coping with chronic stress and sustaining reproductive function.

Reconsidering Luria's speech mediation: Verbalization and haptic picture identification in children with congenital total blindness.

Current accounts of behavioral and neurocognitive correlates of plasticity in blindness are just beginning to incorporate the role of speech and verbal production. We assessed Vygotsky/Luria's speech mediation hypothesis, according to which speech activity can become a mediating tool for perception of complex stimuli, specifically, for encoding tactual/haptic spatial patterns which convey pictorial information (haptic pictures). We compared verbalization in congenitally totally blind (CTB) and age-matched sighted but visually impaired (VI) children during a haptic picture naming task which included two repeated, test-retest, identifications. The children were instructed to explore 10 haptic schematic pictures of objects (e.g., cup) and body parts (e.g., face) and provide (without experimenter's feedback) their typical name. Children's explorations and verbalizations were videorecorded and transcribed into audio segments. Using the Computerized Analysis of Language (CLAN) program, we extracted several measurements from the observed verbalizations, including number of utterances and words, utterance/word duration, and exploration time. Using the Word2Vec natural language processing technique we operationalized semantic content from the relative distances between the names provided. Furthermore, we conducted an observational content analysis in which three judges categorized verbalizations according to a rating scale assessing verbalization content. Results consistently indicated across all measures that the CTB children were faster and semantically more precise than their VI counterparts in the first identification test, however, the VI children reached the same level of precision and speed as the CTB children at retest. Overall, the task was harder for the VI group. Consistent with current neuroscience literature, the prominent role of speech in CTB and VI children's data suggests that an underlying cross-modal involvement of integrated brain networks, notably associated with Broca's network, likely also influenced by Braille, could play a key role in compensatory plasticity via the mediational mechanism postulated by Luria.

A non-hallucinogenic LSD analog with therapeutic potential for mood disorders.

Hallucinations limit widespread therapeutic use of psychedelics as rapidly acting antidepressants. Here we profiled the non-hallucinogenic lysergic acid diethylamide (LSD) analog 2-bromo-LSD (2-Br-LSD) at more than 33 aminergic G protein-coupled receptors (GPCRs). 2-Br-LSD shows partial agonism at several aminergic GPCRs, including 5-HT2A, and does not induce the head-twitch response (HTR) in mice, supporting its classification as a non-hallucinogenic 5-HT2A partial agonist. Unlike LSD, 2-Br-LSD lacks 5-HT2B agonism, an effect linked to cardiac valvulopathy. Additionally, 2-Br-LSD produces weak 5-HT2A ß-arrestin recruitment and internalization in vitro and does not induce tolerance in vivo after repeated administration. 2-Br-LSD induces dendritogenesis and spinogenesis in cultured rat cortical neurons and increases active coping behavior in mice, an effect blocked by the 5-HT2A-selective antagonist volinanserin (M100907). 2-Br-LSD also reverses the behavioral effects of chronic stress. Overall, 2-Br-LSD has an improved pharmacological profile compared with LSD and may have profound therapeutic value for mood disorders and other indications.