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Abstract: In this editorial, we discuss the neurobiological processes underlying the early emergence of awareness that we term the “when” and “how” the mind comes to live inside the body. We describe an accumulative developmental process starting during embryonic life and continuing to fetal and postnatal development, of coupling of heart rate, body movements, and sleep states on the behavioral level with underlying mechanisms on the structural, functional, cellular, and molecular levels. A developmental perspective is proposed based on Perceptual Control Theory (PCT). This includes a developing sequence of modules starting from early sensing of neural intensities to early manifestation of human mindful capacities. We also address pharmacological treatments administered to preterm infants, which may interfere with this development, and highlight the need to consider this potential “side effect” of current pharmaceuticals when developing novel pharmacogenomic treatments.

Background While pharmacological treatments for positive symptoms of schizophrenia are widely used, their beneficial effect on negative symptoms, particularly social impairment, is insufficiently studied. Therefore, there is an increasing interest in preclinical research of potentially beneficial treatments, with mixed results. The current review aims to evaluate the efficacy of available treatments for social deficits in different animal models of schizophrenia. Study Design A systematic literature search generated 145 outcomes for the measures “total time” and “number” of social interactions. Standardized mean differences (SMD) and 95% confidence interval (CI) were calculated, and heterogeneity was tested using Q statistics in a random-effect meta-analytic model. Given the vast heterogeneity in effect sizes, the animal model, treatment group, and sample size were all examined as potential moderators. Study Results The results showed that in almost all models, treatment significantly improved social deficit (total time: SMD = 1.24; number: SMD = 1.1). The moderator analyses discovered significant subgroup differences across models and treatment subgroups. Perinatal and adult pharmacological models showed the most substantial influence of treatments on social deficits, reflecting relative pharmacological validity. Furthermore, atypical antipsychotic drugs had the highest SMD within each model subgroup. Conclusions Our findings indicate that the improvement in social interaction behaviors is dependent on the animal model and treatment family used. Implications for the preclinical and clinical fields are discussed.

Background: The Coronavirus disease 19 (COVID-19)-related psychiatric burden partly results from prolonged social stress world-wide. Studies have examined the psychiatric impact of COVID-19 on Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM 5) and International Classification of Diseases 11th Revision (ICD-11) categories, implicating multiple diagnoses, complicating clinical management. Aim: To verify whether COVID-19-related psychopathology spans multiple DSM-5 and ICD-11 diagnoses, but not in a random pattern. Consequently, empirical analysis of the multiple associated symptoms will better describe COVID-19-related psychopathology. Methods: We conducted a bi-national study during the first surge of the pandemic: an Italian sample (n = 21217, studied March-April 2020); and three representative longitudinal samples from Israel (n = 1276, 1189, and 1432 respectively, studied May-July 2020). Data in Italy were collected by a national internet-based survey with an initially approached sample of about one million persons and in Israel by the Israeli Central Bureau of Statistics using probability-based national representative sampling. Data analysis focused on the frequency and patterns of reported multiple mental health symptoms. Results: Combinations with all symptoms were more prevalent than combinations with fewer symptoms, with no majorities-minorities differences in both countries, demonstrating the generalizability of the transdiagnostic pattern of mental health issues in both nations. A history of previous mental disorder (Italian study) and an increase in symptom prevalence over time (Israel study) were associated with an increased number of symptoms. Conclusions: Based on finding correlated symptom diversity spanning conventional diagnostic categories, we suggest that the pattern of mental health issues associated with the COVID-19 pandemic is transdiagnostic. Conclusion: The findings have implications for improving prevention and treatment of COVID-19 related psychopathology and for post-pandemic times in conditions resulting from multiplicity of stressors with mixed symptomatology in the clinical picture.

Background: Most people often consume alcohol cumulatively and gradually. Yet almost scientific knowledge about alcohol’s acute effects on cognition, behavior, and affect stems from laboratory studies that employ a single beverage administration procedure. Objective: This study tests the hypothesis that alcohol’s acute effects depend on both methods of administration and alcohol blood level. We introduce a new laboratory procedure for studying cumulative alcohol drinking and examine alcohol’s effects on emotion recognition as a function of both alcohol administration method and alcohol blood level. Methods: Participants were recruited for one of two studies. One study employed a between-subject design using a single alcoholic dose. Participants were randomly assigned to drink either placebo (0.00%), low (0.03%), moderate (0.06%), or high (0.09%) alcohol levels. The second study employed a within-subject design using a cumulative alcoholic administration method, in which each participant drank four drinks (placebo, followed by three alcoholic drinks). Both groups reached similar breath alcohol concentrations. In both studies, participants attended a single study session, in which emotion recognition was examined following alcohol administration. Results: Single alcoholic beverage administration method caused greater impairment in emotion recognition ability, specifically for anger, happiness, and fear, as compared with cumulative administration method, even though breath alcohol levels were similar in both conditions. Conclusions: This paper presents questions concerning the internal validity of previous laboratory studies that use a single beverage administration procedure. Insights into the effects of alcohol on behavior, as well as regarding our knowledge about models of addiction are presented.

The clinical presentation that emerges from the extensive coronavirus disease 2019 (COVID-19) mental health literature suggests high correlations among many conventional psychiatric diagnoses. Arguments against the use of multiple comorbidities for a single patient have been published long before the pandemic. Concurrently, diagnostic recommendations for use of transdiagnostic considerations for improved treatment have been also published in recent years. In this review, we pose the question of whether a transdiagnostic mental health disease, including psychiatric and neuropsychiatric symptomology, has emerged since the onset of the pandemic. There are many attempts to identify a syndrome related to the pandemic, but none of the validated scales is able to capture the entire psychiatric and neuropsychiatric clinical presentation in infected and non-infected individuals. These scales also only marginally touch the issue of etiology and prevalence. We suggest a working hypothesis termed Complex Stress Reaction Syndrome (CSRS) representing a global psychiatric reaction to the pandemic situation in the general population (Type A) and a neuropsychiatric reaction in infected individuals (Type B) which relates to neurocognitive and psychiatric features which are part (excluding systemic and metabolic dysfunctions) of the syndrome termed in the literature as long COVID. We base our propositions on multidisciplinary scientific data regarding mental health during the global pandemic situation and the effects of viral infection reviewed from Google Scholar and PubMed between February 1, 2022 and March 10, 2022. Search in-clusion criteria were "mental health", "COVID-19" and "Long COVID", English language and human studies only. We suggest that this more comprehensive way of understanding COVID-19 complex mental health reactions may promote better prevention and treatment and serve to guide implementation of recommended administrative regulations that were recently published by the World Psychiatric Association. This review may serve as a call for an international investigation of our working hypothesis.

Depression and anxiety disorders are two of the most common and growing mental health concerns in adolescents. Consequently, antidepressant medication (AD) use has increased widely during the last decades. Several classes of antidepressants are used mainly to treat depression, anxiety, and obsessive-compulsive disorders by targeting relevant brain neurochemical pathways. Almost all randomized clinical trials of antidepressants examined patients with no concomitant medications or drugs. This does not address the expected course of therapy and outcome in cannabis users. Cannabis is the most commonly used illicit substance globally. Substantial changes in its regulation are recently taking place. Many countries and US states are becoming more permissive towards its medical and recreational use. The psychological and physiological effects of cannabis (mainly of its major components, tetrahydrocannabinol (THC) and cannabidiol (CBD)) have been extensively characterized. Cannabis use can be a risk factor for depressive and anxiety symptoms, but some constituents or mixtures may have antidepressant and/or anxiolytic potential. The aim of this literature review is to explore whether simultaneous use of AD and cannabis in adolescence can affect AD treatment outcomes. Based on the current literature, it is reasonable to assume that antidepressants are less effective for adolescents with depression/anxiety who frequently use cannabis. The mechanisms of action of antidepressants and cannabis point to several similarities and conjunctions that merit future investigation regarding the potential effectiveness of antidepressants among adolescents who consume cannabis regularly.

Background and objectives Stressors related to the COVID-19 pandemic are risk factors for psychopathology, but psychosocial protective factors might play a crucial role in buffering the pathogenic effects of the outbreak. Design In the current study, we examined the association of inner resources and potential external sources of support for coping with the pandemic and related lockdowns to mental health during the pandemic, while controlling for sociodemographic variables as covariates. Methods We tested the model in a probability-based internet survey of a representative sample of the Israeli adult population (N = 812) conducted during the COVID-19 pandemic. Results Perceived support in close relationships was negatively associated with the intensity of depression, anxiety, obsessive-compulsive disorder (OCD) and post-traumatic stress disorder (PTSD). Larger rings of potential support such as perceived belongingness to a community and trust in government were also negatively related to anxiety and depression but were positively associated with the intensity of OCD and PTSD. Conclusions Findings support the "tend and befriend" theory in the social distancing era and highlight the importance of keeping personal relationships alive when facing a mass trauma.

We compared retinal layers' thickness between apolipoprotein E (Participants (N = 245) underwent spectral domain optical coherence tomography. Multivariate analyses of covariance adjusting for age, sex, education, and best corrected vision acuity was used to compare retinal thickness betweenParticipants' mean age was 59.60 (standard deviation = 6.42) with 66.4% women and 32.2%A thicker macula is observed already in midlife asymptomatic

The transition to fatherhood may be challenged with anxiety and trepidation. A high prevalence has been found for paternal depression and it is reactive to maternal depression. This review aims to address potential sources of paternal depression, which may have adverse consequences on child development. We describe through three hypotheses how fathers may be at risk of depression during the transition to fatherhood: (1) psychological (interacting with ecological systems); (2) brain functional∖structural changes; and (3) (epi)genomic. We propose that paternal stressful experiences during the transition to fatherhood may be the source for paternal depression through direct stressful paternal experiences or via (potential, currently debated) nonexperienced (by the father) epigenomic transgenerational transmission. On the other hand, we suggest that resilient fathers may undergo a transient dysphoric period affected by identifying with the newborn's vulnerability as well as with the mother's postpartum vulnerability resulting in "paternity blues." In accordance with recent views on paternal "heightened sensitivity" toward the infant, we propose that the identification of both parents with the vulnerability of the newborn creates a sensitive period of Folie a Deux (shared madness) which may be a healthy transient, albeit a quasi-pathological period, recruited by the orienting response of the newborn for survival.

Summary Ultraviolet (UV) light affects endocrinological and behavioral aspects of sexuality via an unknown mechanism. Here we discover that ultraviolet B (UVB) exposure enhances the levels of sex-steroid hormones and sexual behavior, which are mediated by the skin. In female mice, UVB exposure increases hypothalamus-pituitary-gonadal axis hormone levels, resulting in larger ovaries; extends estrus days; and increases anti-Mullerian hormone (AMH) expression. UVB exposure also enhances the sexual responsiveness and attractiveness of females and male-female interactions. Conditional knockout of p53 specifically in skin keratinocytes abolishes the effects of UVB. Thus, UVB triggers a skin-brain-gonadal axis through skin p53 activation. In humans, solar exposure enhances romantic passion in both genders and aggressiveness in men, as seen in analysis of individual questionaries, and positively correlates with testosterone level. Our findings suggest opportunities for treatment of sex-steroid-related dysfunctions., Graphical abstract, Highlights • UVB exposure increases circulating sex-steroid levels in mice and humans • UVB exposure enhances female attractiveness and receptiveness toward males • UVB exposure increases females’ estrus phase, HPG axis hormones, and follicle growth • Skin p53 regulates UVB-induced sexual behavior and ovarian physiological changes, Parikh et al. find that UVB exposure triggers a skin-brain-gonadal axis through skin p53 activation. UVB exposure increases in female mice sexual responsiveness and attractiveness, hypothalamus-pituitary-gonadal axis hormone levels, ovary size, and estrus duration, as well as male-female interactions. Solar exposure in humans enhances romantic passion and positively correlates with male testosterone levels.

Sexual dimorphisms are responsible for profound metabolic differences in health and behavior. Whether males and females react differently to environmental cues, such as solar ultraviolet (UV) exposure, is unknown. Here we show that solar exposure induces food-seeking behavior, food intake, and food-seeking behavior and food intake in men, but not in women, through epidemiological evidence of approximately 3,000 individuals throughout the year. In mice, UVB exposure leads to increased food-seeking behavior, food intake and weight gain, with a sexual dimorphism towards males. In both mice and human males, increased appetite is correlated with elevated levels of circulating ghrelin. Specifically, UVB irradiation leads to p53 transcriptional activation of ghrelin in skin adipocytes, while a conditional p53-knockout in mice abolishes UVB-induced ghrelin expression and food-seeking behavior. In females, estrogen interferes with the p53–chromatin interaction on the ghrelin promoter, thus blocking ghrelin and food-seeking behavior in response to UVB exposure. These results identify the skin as a major mediator of energy homeostasis and may lead to therapeutic opportunities for sex-based treatments of endocrine-related diseases.

The current study explores the therapeutic potential of Cannabidiol (CBD), a compound in the Cannabis plant, using both sexes of 2 “depressive-like” genetic models, Wistar Kyoto (WKY) and Flinders Sensitive Line (FSL) rats. Rats ingested CBD (30 mg/kg) orally. In the saccharin preference test, following a previous report of a pro-hedonic effect of CBD in male WKY, we now found similar results in female WKY. CBD also decreased immobility in the forced swim test in males (both strains) and in female WKY. These findings suggest a role for CBD in treating mental disorders with prominent symptoms of helplessness and anhedonia.

Nitric Oxide (NO) and its precursor l-arginine were found to inhibit feeding in rats with a low motivation to eat, as they do in Aplysia. In rats that are relatively satiated, treatment with an NO blocker increased feeding, and treatment with an NO donor or with either of 2 doses of l-arginine inhibited feeding. NO and l-arginine modulated several parameters of feeding, such as the total duration of appetitive behaviors, the time spent feeding, the quantity of food eaten and the number of feeding bouts. The inhibitory effect of l-arginine on feeding could not be attributed to changes in locomotion. These data indicate that satiation is partially mediated by increased production of NO. NADPH-Diaphorase histochemical staining, which is specific for tissues actively producing NO, showed significantly greater staining in satiated compared to hungry rats in all 4 hypothalamic nuclei (paraventricular and arcuate nuclei, lateral and ventromedial hypothalamus) that were examined. l-arginine may act as a regulator of feeding by controlling NO production in several hypothalamic nuclei, specifically under condition of a low feeding motivation.

Depression, the most prevalent psychiatric disorder in the Western world, is characterized by increased negative affect (i.e., depressed mood, cost value increase) and reduced positive affect (i.e., anhedonia, reward value decrease), fatigue, loss of appetite, and reduced psychomotor activity except for cases of agitative depression. Some forms, such as post-partum depression, have a high risk for suicidal attempts. Recent studies in humans and in animal models relate major depression occurrence and reoccurrence to alterations in dopaminergic activity, in addition to other neurotransmitter systems. Imaging studies detected decreased activity in the brain reward circuits in major depression. Therefore, the location of dopamine receptors in these circuits is relevant for understanding major depression. Interestingly, in cortico–striatal–dopaminergic pathways within the reward and cost circuits, the expression of dopamine and its contribution to reward are modulated by endocannabinoid receptors. These receptors are enriched in the striosomal compartment of striatum that selectively projects to dopaminergic neurons of substantia nigra compacta and is vulnerable to stress. This review aims to show the crosstalk between endocannabinoid and dopamine receptors and their vulnerability to stress in the reward circuits, especially in corticostriatal regions. The implications for novel treatments of major depression are discussed.

The COVID-19 pandemic exposed the field of psychotherapy to the need to provide treatment remotely. We discuss the question of whether remote therapy can be curative and if the electronic device used to manage these sessions unites or separates the therapist and the patient. We term the electronic device as 'the inanimate third' in the therapeutic process and discuss the objectivity of the device as opposed to the subjective emotional processes involved. We deal with emotional themes relevant to the COVID-19 pandemic and associated social distancing practices, such as longing, loneliness, the perception of the future and the lost past, and the efficacy of the therapeutic stimulation of fantasy and hope. We also evaluate the possibility of existing transference and countertransference processes while working remotely. We suggest the term 'social paradox' to describe the situation in which an objective entity such as the digital media symbolizes both distance and intimacy as well as separation and unity. We conclude by stating that containment of the social paradox by the therapeutic dialogue is possible as the existence of the dialogue eliminates elements of the paradox.

Background and aim Studies have shown that increased maternal cortisol level is associated with child adverse health outcomes. Hair cortisol (HC) is suitable for assessing long-term circulating cortisol concentration. Only two previous studies reported beneficial associations between cortisol and residential greenness during pregnancy and no study focused on the first trimester. Our aim was to evaluate the association between residential greenness and first trimester HC levels among pregnant women in Israel. Methods Women were recruited during second and third trimesters. Hair samples were collected from the scalp and retrospective HC levels during the first trimester were quantified for 217 women. HC levels were natural log transformed and outliers were excluded. Based on geocoded birth address, small area sociodemographic status (SES) and mean residential surrounding greenness were calculated using high-resolution satellite-based Normalised Difference Vegetation Index (NDVI) data at 100, 300 and 500-m buffers in a cross-sectional approach. In addition, longitudinal exposure to mean greenness during a week preconception and during the first trimester were calculated. Missing covariates were imputed and linearity of the associations were evaluated. Generalized linear models were used to estimate the crude and adjusted associations controlled for the relevant covariates. Results After exclusion of outliers, for 211 women, crude and adjusted beneficial associations between exposure to higher mean NDVI and HC levels were observed for all the exposure measures. An increase in 1 interquartile range of greenness (100 m buffer) was associated with a statistically significant lower estimated natural log mean HC level (−0.27 95% CI: −0.44; −0.11). The associations were robust to adjustment for covariates. The findings were consistent for different buffers, for the longitudinal approach, when all observations were included in the analysis and slightly stronger associations were observed for women with addresses geocoded at the home or street level. For most of the exposure measures, stronger associations were observed among those of lower sociodemographic status. Conclusion Our findings that more greenness associated with reduced maternal cortisol levels measured in the hair during the first trimester, could have substantial implications for urban planners and public health professional. If our observations will be replicated, it may present a useful avenue for public-health intervention to promote health through the provision of greenness exposure during early pregnancy, specifically to disadvantage populations.

Feeding inhibition caused by satiation in rats is partially mediated by the unconventional neurotransmitter nitric oxide (NO). Thus, in satiated rats blocking NO production increases feeding, and treatment with the NO precursor l-arginine or with an NO donor reduces feeding beyond that caused by satiation. Do NO and l-arginine also inhibit feeding when feeding motivation is high? When feeding motivation in satiated animals was hedonically increased by offering a highly attractive food, blocking NO production reduced the quantity eaten, rather than increasing it, indicating that hedonic aspects of food are partially mediated by NO. Increasing NO via an NO donor or l-arginine did not further increase the quantity eaten, indicating a ceiling effect. The NO donor, but not l-arginine, also decreased some motivation-dependent parameters of feeding. When feeding motivation was increased by hunger, quantities of food eaten were unaffected by an NO donor, blocker or precursor, with only the blocker of NO production affecting feeding patterning. We also examined effects on feeding of dissolving l-arginine in drinking water over 3 weeks. Chronic l-arginine administration had different effects during the first and in subsequent weeks, increasing feeding at first, but not later. The data indicate that NO has complex, state dependent effects on both the quantity of food eaten, and on patterns of feeding, probably reflecting different sites and mechanisms of action in the nervous system.

Borderline Personality Disorder (BPD) is a chronic debilitating psychiatric disorder characterized mainly by emotional instability, chaotic interpersonal relationships, cognitive disturbance (e.g., dissociation and suicidal thoughts) and maladaptive behaviors. BPD has a high rate of comorbidity with other mental disorders and a high burden on society. In this review, we focused on two compromised brain regions in BPD - the hypothalamus and the corticolimbic system, emphasizing the involvement and potential contribution of the endocannabinoid system (ECS) to improvement in symptoms and coping. The hypothalamus-regulated endocrine axes (hypothalamic pituitary – gonadal, thyroid & adrenal) have been found to be dysregulated in BPD. There is also substantial evidence for limbic system structural and functional changes in BPD, especially in the amygdala and hippocampus, including cortical regions within the corticolimbic system. Extensive expression of CB1 and CB2 receptors of the ECS has been found in limbic regions and the hypothalamus. This opens new windows of opportunity for treatment with cannabinoids such as cannabidiol (CBD) as no other pharmacological treatment has shown long-lasting improvement in the BPD population to date. This review aims to show the potential role of the ECS in BPD patients through their most affected brain regions, the hypothalamus and the corticolimbic system. The literature reviewed does not allow for general indications of treatment with CBD in BPD. However, there is enough knowledge to indicate a treatment ratio of a high level of CBD to a low level of THC. A randomized controlled trial investigating the efficacy of cannabinoid based treatments in BPD is warranted.

Ultraviolet (UV) light affects endocrinological and behavioral aspects of human sexuality via an unknown mechanism. Using a unique male-female comparative approach, we discovered that the sexual behavioral and hormonal features enhanced by UVB are mediated by the skin. In mice, UV exposure increases hypothalamus-pituitary-gonadal axis hormone levels, resulting in enhanced ovary size, extended estrus days, and anti-Mullerian hormone (AMH) expression. It likewise enhances sexual responsiveness and attractiveness of females and heterosexual interactions of both males and females. Conditional knockout of p53 specifically in skin keratinocytes abolished UV’s effects. In humans, UV exposure enhanced romantic passion in both genders, increased testosterone levels in men and correlated with heightened plasma AMH levels in women. Our data, revealing that UVB triggers a skin-brain-gonadal axis through skin p53 activation, offers therapeutic opportunities for sex-steroid-related dysfunctions. We speculate that during human furless skin evolution, the skin became the front-line regulator of the response to UVB.

Obesity and its associated complications have reached epidemic proportions in the US and worldwide, highlighting the need for new and more effective treatments. While the neuropeptide oxytocin (OXT) is well recognized for its peripheral effects on reproductive behavior, release of OXT from somatodendrites and axonal terminals within the central nervous system (CNS) is also implicated in the control of control of energy balance. In this review we summarize historical data highlighting the effects of exogenous OXT as a short-term regulator of food intake in a context specific manner and the receptor populations that may mediate these effects. We also describe what is known about the physiological role of endogenous OXT in the control of energy balance and whether serum and brain levels of OXT relate to obesity on a consistent basis across animal models and humans with obesity. We describe recent data on the effectiveness of chronic CNS administration of OXT to decrease food intake and weight gain or to elicit weight loss in diet-induced obese (DIO) and genetically obese mice and rats. Of clinical importance is the finding that both chronic central and peripheral OXT treatment evoke weight loss in obese animal models with impaired leptin signaling at doses that are not associated with visceral illness, tachyphylaxis, or adverse cardiovascular effects. Moreover, these results have been largely recapitulated following chronic subcutaneous or intranasal treatment in DIO nonhuman primates (rhesus monkeys) and obese humans, respectively. We also identify plausible mechanisms that contribute to the effects of OXT on body weight and glucose homeostasis in rodents, nonhuman primates, and humans. We conclude by describing ongoing challenges that remain in order for OXT-based therapeutics to be used as a long-term strategy to treat obesity in humans.

Background Several studies have shown inconsistent associations between anxiety during pregnancy and adverse pregnancy outcome. This inconsistency may be due to lack of controlling for the timing and type of maternal anxiety. We aimed to isolate a specific type of anxiety - maternal anxiety propensity, which is not directly related to pregnancy, and evaluate its association with adverse pregnancy outcome. Methods We conducted a prospective observational study of 512 pregnant women, followed to delivery. The trait anxiety scale of the State-Trait Anxiety Inventories was used in order to detect a propensity towards anxiety. The association between anxiety propensity (defined as trait-anxiety subscale score above 38) and adverse pregnancy outcome was evaluated. Primary outcome was a composite outcome including preterm birth prior to 37 gestational weeks, hypertensive disorders in pregnancy, small for gestational age newborn and gestational diabetes mellitus. Secondary outcomes were each one of the above mentioned gestational complications. Results There were no significant between-group differences in adverse pregnancy outcomes, including the rate of preterm birth, hypertensive disorders, small for gestational age, gestational diabetes or a composite outcome of them all. Conclusion Anxiety propensity is not associated with adverse pregnancy outcome. Electronic supplementary material The online version of this article (10.1186/s12884-018-1925-8) contains supplementary material, which is available to authorized users.

Purpose: To identify early retinal biomarkers for Alzheimer disease (AD) using multimodal imaging. Methods: Infra-red (IR) and multicolor fundus imaging and spectral domain optic coherence tomography (SD-OCT) were performed in 108 offspring of AD patients (FH+) and 44 age-matched controls (FH-). All subjects were tested for cognitive function by executive function and episodic memory tests. MRI brain imaging was performed on a 3T MRI. Results: In FH+ subjects, lower performance in memory was associated with thicker peri-papillary temporal-superior RNFL (r=-0.220; p=.016). In FH- subjects, the correlation was in the opposite direction (r=0.335; p=.013). In FH+, left Hippocampal volume was associated with larger total macular thickness (r=0.212; p=.028), as well as thicker macular RNFL (r=0.216; p=.025), macular GCL (r=0.221; p=.022), and macular IPL (r=0.285, p=.003). Similar results were found in the right eye. Conclusions: The thickness of inner retinal layers and peripapillary RNFL are associated with cognitive functioning and hippocampal volume in asymptomatic subjects at high risk for AD and may present novel biomarkers for very early detection of AD.

The endocannabinoid system (ECS) critically regulates stress responsivity and emotional behavior throughout development. It regulates anxiety-like behaviors in humans and animal models. In addition, it is sensitive to early life stress at the gene expression level in a sex-dependent and region-dependent manner, and these changes are already evident in the adolescent brain. The ECS modulates the neuroendocrine and behavioral effects of stress, and is also capable of being affected by stress exposure itself. Early life stress interferes with the development of corticolimbic circuits, a major location of endocannabinoid receptors, and increases vulnerability to adult psychopathology. Early life stress alters the ontogeny of the ECS, resulting in a sustained deficit in its function, particularly within the hippocampus. Specifically, exposure to early stress results in bidirectional changes in anandamide and 2-AG tissue levels within the amygdala and hippocampus and reduces hippocampal endocannabinoid function at puberty. CB1 receptor densities across all brain regions are downregulated later in life following exposure to early life stress. Manipulations affecting the glucocorticoid and the endocannabinoid systems persistently adjust individual emotional responses and synaptic plasticity. This review aims to show the bidirectional trajectories of endocannabinoid modulation of emotionality in reaction to early life stress.

OBJECTIVES Abnormal brain connectivity has been described in depressive disorder. However, these studies are correlational or cross-sectional and their design does not examine causal relationships. We aimed to investigate structural connectivity in a genetic rat model of depression. METHODS Using diffusion tensor imaging (DTI), we reconstructed white matter tracts and analysed fractional anisotropy (FA) and diffusivity indices (mean, axial and radial) to investigate structural connectivity in fibre tracts implicated in major depression: the corpus callosum, fornix, cingulum and anterior commissures. RESULTS Tractography-based analysis revealed that, compared to Wistar control rats, the Wistar-Kyoto strain (WKY) rat model of depression exhibited decreased connectivity, manifested by decreased FA in the corpus callosum, right and left anterior commissures. A statistical trend of decreased FA was observed in both the right and left cingulum. Increased diffusivity (mean diffusion) was detected in both the corpus callosum and the fornix of WKY rats compared to controls. Voxel-based analysis confirmed differences between WKY and controls in the regions investigated. CONCLUSIONS Decreased connectivity in a genetic rat model of depression corroborates the findings in patients suffering from major depression suggesting that the vulnerability for developing depression is mainly polygenic and less likely to be due to childhood adversity per se.

Olanzapine-induced weight gain is associated with atherosclerosis, hypertension, dyslipidemia, and diabetes. We synthesized a novel antipsychotic drug (PGW5) possessing an olanzapine moiety linked to sarcosine, a glycine transporter 1 inhibitor. In this study, we compared the metabolic effects of PGW5 and olanzapine in a female rat model of weight gain. Female rats were treated daily with oral olanzapine (4 mg/kg), PGW5 (25 mg/kg), or vehicle for 16 days. Behavioral tests were conducted on days 12-14. Biochemical analyses were performed at the end of the treatment. A significant increase in body weight was observed in the olanzapine-treated group, while the PGW5 group did not differ from the controls. The open field test showed hypo-locomotion in the olanzapine-treated animals as compared to PGW5 and control groups. A significant increase in hypothalamic protein expression of the neuropeptide Y5 receptor and a decrease in pro-opiomelanocortin messenger ribonucleic acid (mRNA) levels were detected following PGW5 treatment, but not after olanzapine administration. PGW5 appears to possess minor metabolic effects compared with the parent compound olanzapine. The differential modulation of brain peptides associated with appetite regulation is possibly involved in the attenuation of metabolic effects by PGW5.