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The mechanisms by which common risk variants of small effect interact to contribute to complex genetic disorders remain unclear. Here, we apply a genetic approach, using isogenic human induced pluripotent stem cells (hiPSCs), to evaluate the effects of schizophrenia-associated common variants predicted to function as brain expression quantitative trait loci (SZ-eQTLs). By integrating CRISPR-mediated gene editing, activation and repression technologies to study one putative SZ-eQTL (FURIN rs4702) and four top-ranked SZ-eQTL genes (FURIN, SNAP91, TSNARE1, CLCN3), our platform resolves pre- and post-synaptic neuronal deficits, recapitulates genotype-dependent gene expression differences, and identifies convergence downstream of SZ-eQTL gene perturbations. Our observations highlight the cell-type-specific effects of common variants and demonstrate a synergistic effect between SZ-eQTL genes that converges on synaptic function. We propose that the links between rare and common variants implicated in psychiatric disease risk constitute a potentially generalizable phenomenon occurring more widely in complex genetic disorders.

17s-Estradiol (E2) is a potent neuromodulator capable of producing changes in inhibitory synaptic transmission by either changing pre-synaptic GABA release or post-synaptic GABAA receptor function. Physiologically, E2 is important for energy homeostasis, influencing food consumption, body weight, adipose tissue metabolism and energy expenditure. E2 may influence energy homeostasis through estrogen receptor-rich regions such as the oval bed nucleus of the stria-terminalis (ovBNST). However, the neurophysiological effects of estradiol within the ovBNST remain largely unknown. Understanding how E2 affects inhibitory transmission may elucidate the ovBNST’s contribution to energy homeostasis. Here, using brain slice electrophysiology, we saw that E2 produced a long-term potentiation (LTP) of GABAA synaptic transmission (LTPGABA) in the ovBNST in male rats. E2 acted on estrogen receptors α and G-protein coupled estrogen receptors (GPER), involved protein kinase activation and required an intact endocannabinoid system. The effects of E2 in males were sensitive to 24 h of food deprivation. In females, E2 was 100-fold more potent at producing LTPGABA ovBNST compared to male rats and involved all three known subtypes of estrogen receptors (ERα, ERs, and GPER). These results demonstrate that E2 is a potent neuromodulator of inhibitory synaptic transmission within the ovBNST of both sexes to potentially regulate energy homeostasis.

Puberty is a period of rapid cortical and neuronal development. Stress exposure during puberty programs the hypothalamic-pituitary-adrenal (HPA) axis responsiveness to future stressors. However, programming can result in an enduring maladaptation of the HPA axis activity and can be associated with long-term anxiety- and depression-like behaviours. Probiotic treatment mitigates the effect of stress on mental health, suggesting that the gut microbiome may mediate the programming of the HPA axis. However, the mechanism underlying this effect remains elusive. Thus, we investigated the effect of probiotic exposure on lipopolysaccharide (LPS)-induced programming of the HPA axis and glucocorticoid receptor (GR) expression in the paraventricular (PVN), basolateral amygdala (BLA), piriform cortex (PIR), and medial prefrontal cortex (mPFC). Male and female mice were exposed to either probiotics or control skim milk and were treated with either saline or LPS during puberty. Prior to euthanasia in adulthood, mice were restrained for 30 min. The results showed that pubertal LPS treatment permanently decreased GR expression in the PVN in milk fed control males. However, pubertal probiotic treatment blocked the LPS-induced decrease in GR expression in males. Given that this effect is limited to males, further research is required to better understand sex differences in the interactions between the gut microbiome and the programming of the HPA axis during puberty. Nevertheless, our findings suggest that the gut microbiome influences the neurophysiology of the HPA axis and mediates its programming in pubertal males. The prevention of GR reduction in the male PVN and PIR using probiotics illustrates the complexity of the gut-brain communication and compels continued investigation.

This paper examines current research into the impact of climate change on wine production and wine tourism, as well as reporting on a set of interviews with wine professionals in the Douro valley of Portugal and the Finger Lakes region of the United States. The literature review and interviews are used to assess the likely impact of climate change on wine production in each region and the expected ability of wine makers to maintain traditional wine styles and grape choices in the face of changing climate. It also explores the possible relationship between traditional wine styles and wine tourism in new and old-world regions. This paper's conclusions suggest the possibility that changes in a traditional wine style would affect wine tourism in a given region. They also conclude that climate change is already affecting traditional wine styles, particularly in Old- world regions of Europe and that wine makers may eventually be unable to sustain a wone style in any region.

Compulsions, defined by debilitating repetitive actions, permeate many mental illnesses and are challenging to treat partly because of a limited understanding of their neurobiological underpinnings. Accumulating evidence suggests the rodent model of Schedule-Induced Polydipsia (SIP) as a promising pre-clinical assay to elucidate the neurobiological and behavioural manifestations of compulsivity. In the rodent SIP paradigm, susceptible rats develop adjunctive excessive drinking when they are chronically food restricted and presented with food pellets according to a fixed-time schedule. We found that normally, bi-directional plasticity of GABA synapses in the oval bed nucleus of the stria terminalis (ovBNST) tightly followed the rats’ satiety state where low-frequency stimulation-induced potentiation (LTPGABA) prevailed in sated rats whilst food restriction uncovered long-term depression (LTDGABA). In rats that developed excessive drinking during SIP, removing the caloric restriction failed at reverting LTDGABA to LTPGABA whereas bi-directional plasticity at ovBNST GABA synapses was unaltered in low-drinking SIP-trained rats. Excessive drinking ceased in polydipsic rats removed from their caloric restriction; however, these rats retained a form of compulsive schedule-induced checking (SIC) and impaired plasticity at ovBNST GABA synapses for several days following termination of the caloric restriction. We conclude that altered bi-directional plasticity at ovBNST GABA synapses is a neurophysiological trace of compulsivity in susceptible rats in the SIP model.

Testosterone can be safely and effectively administered to estrogen-treated post-menopausal women experiencing hypoactive sexual desire. However, in the United States and Canada, although it is often administered off-label, testosterone co-administered with estradiol is not a federally approved treatment for sexual arousal/desire disorder, partly because its mechanism is poorly understood. One possible mechanism involves the aromatization of testosterone to estradiol. In an animal model, the administration of testosterone propionate (TP) given in combination with estradiol benzoate (EB) significantly increases sexually appetitive behaviors (i.e., solicitations and hops/darts) in ovariectomized (OVX) Long-Evans rats, compared to those treated with EB-alone. The goal of current study was to test whether blocking aromatization of testosterone to estradiol would disrupt the facilitation of sexual behaviors in OVX Long-Evans rats, and to determine group differences in Fos immunoreactivity within brain regions involved in sexual motivation and reward. Groups of sexually experienced OVX Long-Evans rats were treated with EB alone, EB+TP, or EB+TP and the aromatase inhibitor Fadrozole (EB+TP+FAD). Females treated with EB+TP+FAD displayed significantly more hops and darts, solicitations and lordosis magnitudes when compared to EB-alone females. Furthermore, TP, administered with or without FAD, induced the activation of Fos-immunoreactivity in brain areas implicated in sexual motivation and reward including the medial preoptic area, ventrolateral division of the ventromedial nucleus of the hypothalamus, the nucleus accumbens core, and the prefrontal cortex. These results suggest that aromatization may not be necessary for TP to enhance female sexual behavior and that EB+TP may act via androgenic pathways to increase the sensitivity of response to male-related cues, to induce female sexual desire.

Amyotrophic lateral sclerosis (ALS) is a complex and fatal neurodegenerative disease for which the causes of disease onset and progression remain unclear. Recent advances in human induced pluripotent stem cell (hiPSC)-based models permit the study of the genetic factors associated with ALS in patient-derived neural cell types, including motor neurons and glia. While astrocyte dysfunction has traditionally been thought to exacerbate disease progression, astrocytic dysfunction may play a more direct role in disease initiation and progression. Such non-cell autonomous mechanisms expand the potential targets of therapeutic intervention, but only a handful of ALS risk-associated genes have been examined for their impact on astrocyte dysfunction and neurodegeneration. This review summarizes what is currently known about astrocyte function in ALS and suggests ways in which hiPSC-based models can be used to more effectively study the role of astrocytes in neurodegenerative disease.