Psychosis susceptibility is mediated in part by the dopaminergic neurotransmitter system. In humans, individual differences in vulnerability for psychosis are reflected in differential sensitivity for psychostimulants such as amphetamine. We hypothesize that the same genes and pathways underlying behavioral sensitization in mice are also involved in the vulnerability to psychosis.

Mutant Wobbler mice are models for human amyotrophic lateral sclerosis (ALS). In addition to spinal cord degeneration, Wobbler mice show high levels of blood corticosterone, hyperactivity of the hypothalamic-pituitary-adrenal axis and abnormalities of the hippocampus. Hypersecretion of glucocorticoids increase hippocampus vulnerability, a process linked to an enriched content of glucocorticoid receptors (GR). Hence, we studied if a selective GR antagonist (CORT108297) with null affinity for other steroid receptors restored faulty hippocampus parameters of Wobbler mice. Three months old genotyped Wobbler mice received s.c. vehicle or CORT108297 during 4 days. We compared the response of doublecortin (DCX)+ neuroblasts in the subgranular layer of the dentate gyrus (DG), NeuN+ cells in the hilus of the DG, glial fibrillary acidic protein (GFAP)+ astrocytes and the phenotype of Iba1+ microglia in CORT108297-treated and vehicle-treated Wobblers. The number of DCX+ cells in Wobblers was lower than in control mice, whereas CORT108297 restored this parameter. After CORT108297 treatment, Wobblers showed diminished astrogliosis, and changed the phenotype of Iba1+ microglia from an activated to a quiescent form. These changes occurred without alterations in the hypercorticosteronemia or the number of NeuN+ cells of the Wobblers. In a separate experiment employing control NFR/NFR mice, treatment with corticosterone for 5 days reduced DCX+ neuroblasts and induced astrocyte hypertrophy, whereas treatment with CORT108297 antagonized these effects. Normalization of neuronal progenitors, astrogliosis and microglial phenotype by CORT108297 indicates the usefulness of this antagonist to normalize hippocampus parameters of Wobbler mice. Thus, CORT108297 opens new therapeutic options for the brain abnormalities of ALS patients and hyperadrenocorticisms.

The common marmoset monkey (Callithrix jacchus), a small non-endangered New World primate native to eastern Brazil, is becoming increasingly used as a non-human primate model in biomedical research, drug development and safety assessment. In contrast to the growing interest for the marmoset as an animal model, the molecular tools for genetic analysis are extremely limited.

Accumulating epidemiological evidence points to the role of genetic background as a modulator of the capacity of adverse early experiences to give rise to mental illness. However, direct evidence of such gene-environment interaction in the context of substance abuse is scarce. In the present study we investigated whether the impact of early life experiences on cocaine intake in adulthood depends on genetic background. In addition, we studied other behavioral dimensions associated with drug abuse, i.e. anxiety- and depression-related behaviors.

Idalopirdine (Lu AE58054) is a high affinity and selective antagonist for the human serotonin 5-HT6 receptor (Ki 0.83nM) in phase III development for mild-to-moderate Alzheimer's disease as an adjunct therapy to acetylcholinesterase inhibitors (AChEIs). We have studied the effects of idalopirdine on extracellular levels of monoamines, glutamate and acetylcholine in the medial prefrontal cortex (mPFC) of freely-moving rats using microdialysis. Idalopirdine (10mg/kg p.o.) increased extracellular levels of dopamine, noradrenaline and glutamate in the mPFC and showed a trend to increase serotonin levels. No effect was observed on acetylcholine levels. The AChEI donepezil (1.3mg/kg s.c.) significantly increased the levels of acetylcholine. Pretreatment with idalopirdine 2h prior to donepezil administration potentiated the effect of donepezil on extracellular acetylcholine levels. The idalopirdine potentiation of donepezil-induced increase in acetylcholine levels was also observed during local infusion of idalopirdine (6µg/ml) into the mPFC by reverse dialysis. The data from the current study may provide a mechanistic model for the pro-cognitive effects observed with administration of idalopirdine in donepezil-treated patients with Alzheimer's disease observed in the phase 2 studies (Wilkinson et al. 2014).

Stress causes activation of the hypothalamic-pituitary-adrenal (HPA) axis, resulting in secretion of corticosteroids which facilitate behavioural adaptation. These effects exerted by corticosteroids are mediated by two brain corticosteroid receptor types, the mineralocorticoid receptor (MR), with a high affinity already occupied under basal conditions and the glucocorticoid receptor (GR), with a low affinity only activated during stress. Here, we studied MR gene haplotypes constituted by the two single nucleotide polymorphisms MR-2G/C (rs2070951) and MRI180V (rs5522). The haplotypes showed differences in cortisol-induced gene transcription and protein expression while the structural variant MRI180V did not affect ligand binding. Moreover, in a well characterized cohort of 166 school teachers these haplotypes have been associated with perceived chronic stress (Trier Inventory for the Assessment of Chronic Stress, TICS) and, in a subgroup of 47 subjects, with ACTH, cortisol and heart rate responses to acute psychosocial stress (Trier Social Stress Test, TSST). MR haplotypes were significantly associated with the TICS scales "excessive demands at work" and "social overload". Subjects homozygous for haplotype MR-2C/MRI180, which in vitro showed highest expression and transactivational activity, displayed the highest salivary cortisol (p<0.001), plasma cortisol (p=0.010), plasma ACTH (p=0.003) and heart rate (p=0.018) responses. It is concluded that the investigated MR haplotypes modulate cortisol-induced gene transcription in vitro. Moreover, these haplotypes may contribute to individual differences in perceived chronic stress as well as neuroendocrine and cardiovascular stress responses.

Sortilin is a type I membrane glycoprotein belonging to the vacuolar protein sorting 10 protein (Vps10p) family of sorting receptors and is most abundantly expressed in the central nervous system. Sortilin has emerged as a key player in the regulation of neuronal viability and has been implicated as a possible therapeutic target in a range of disorders. Here, the identification of AF40431, the first reported small-molecule ligand of sortilin, is reported. Crystals of the sortilin-AF40431 complex were obtained by co-crystallization and the structure of the complex was solved to 2.7 Å resolution. AF40431 is bound in the neurotensin-binding site of sortilin, with the leucine moiety of AF40431 mimicking the binding mode of the C-terminal leucine of neurotensin and the 4-methylumbelliferone moiety of AF40431 forming π-stacking with a phenylalanine.

The 5-HT6 receptor is a promising target for cognitive disorders, in particular for Alzheimer's disease (AD) and other CNS disorders. The high-affinity and selective 5-HT6 receptor antagonist idalopirdine (Lu AE58054) is currently in development for mild-moderate AD as adjunct therapy to acetylcholinesterase inhibitors (AChEIs). We studied the effects of idalopirdine alone and in combination with the AChEI donepezil on brain activity using BOLD (Blood Oxygen Level Dependent) functional magnetic resonance imaging (fMRI) in the awake rat. Idalopirdine (2 mg/kg, i.v.) alone had a modest effect on brain activity, resulting in activation of eight brain regions at the peak response. Of these, the cholinergic diagonal band of Broca, the infralimbic cortex, the ventral pallidum, the nucleus accumbens shell, and the magnocellular preoptic area were shared with the effects of donepezil (0.3 mg/kg, i.v.). Donepezil alone activated 19 brain regions at the peak response, including several cortical regions, areas of the septo-hippocampal system and the serotonergic raphe nucleus. When idalopirdine and donepezil were combined, there was a robust stimulation pattern with activation of 36 brain regions spread across the extended-amygdala-, striato-pallidal, and septo-hippocampal networks as well as the cholinergic system. These findings indicate that, whilst idalopirdine and donepezil recruit a number of overlapping regions including one of the forebrain cholinergic nuclei, the synergistic effect of both compounds extends beyond the cholinergic system and the effects of donepezil alone toward recruitment of multiple neural circuits and neurotransmitter systems. These data provide new insight into the mechanisms via which idalopirdine might improve cognition in donepezil-treated AD patients.

Glucocorticoids are crucial for stress-coping, resilience, and adaptation. However, if the stress hormones become dysregulated, the vulnerability to stress-related diseases is enhanced. In this brief review, we discuss the role of glucocorticoids in the pathogenesis of neurodegenerative disorders in both human and animal models, and focus in particular on amyotrophic lateral sclerosis (ALS). For this purpose, we used the Wobbler animal model, which mimics much of the pathology of ALS including a dysfunctional hypothalamic-pituitary-adrenal axis. We discuss recent studies that demonstrated that the pathological cascade characteristic for motoneuron degeneration of ALS is mimicked in the genetically selected Wobbler mouse and can be attenuated by treatment with the selective glucocorticoid receptor antagonist (GRA) CORT113176. In long-term treatment (3 weeks) GRA attenuated progression of the behavioral, inflammatory, excitatory, and cell-death-signaling pathways while increasing the survival signal of serine-threonine kinase (pAkt). The action mechanism of the GRA may be either by interfering with GR deactivation or by restoring the balance between pro- and anti-inflammatory signaling pathways driven by the complementary mineralocorticoid receptor (MR)- and GR-mediated actions of corticosterone. Accordingly, GR antagonism may have clinical relevance for the treatment of neurodegenerative diseases.

Glucocorticoids, secreted by the adrenals in response to stress, profoundly affect structure and plasticity of neurons. Glucocorticoid action in neurons is mediated by glucocorticoid receptors (GR) that operate as transcription factors in the regulation of gene expression and either bind directly to genomic glucocorticoid response elements (GREs) or indirectly to the genome via interactions with bound transcription factors. These two modes of action, respectively called transactivation and transrepression, result in the regulation of a wide variety of genes important for neuronal function. The objective of the present study was to identify genome-wide glucocorticoid receptor binding sites in neuronal PC12 cells using Chromatin ImmunoPrecipitation combined with next generation sequencing (ChIP-Seq).

Social interaction with unknown individuals requires fast processing of information to decide whether it is friend or foe. This process of discrimination and decision-making is stressful and triggers secretion of corticosterone activating mineralocorticoid receptor (MR) and glucocorticoid receptor (GR). The MR is involved in appraisal of novel experiences and risk assessment. Recently, we have demonstrated in a dual-solution memory task that MR plays a role in the early stage of information processing and decision-making. Here we examined social approach and social discrimination in male and female mice lacking MR from hippocampal-amygdala-prefrontal circuitry and controls. The social approach task allows the assessment of time spent with an unfamiliar mouse and the ability to discriminate between familiar and unfamiliar conspecifics. The male and female test mice were both more interested in the social than the non-social experience and deletion of their limbic MR increased the time spent with an unfamiliar mouse. Unlike controls, the male MR(CaMKCre) mice were not able to discriminate between an unfamiliar and the familiar mouse. However, the female MR mutant had retained the discriminative ability between unfamiliar and familiar mice. Administration of the MR antagonist RU28318 to male mice supported the role of the MR in the discrimination between an unfamiliar mouse and a non-social stimulus. No effect was found with a GR antagonist. Our findings suggest that MR is involved in sociability and social discrimination in a sex-specific manner through inhibitory control exerted putatively via limbic-hippocampal efferents. The ability to discriminate between familiar and unfamiliar conspecifics is of uttermost importance for territorial defense and depends on a role of MR in decision-making.

Stressful life experiences facilitate responsiveness to psychostimulant drugs. While there is ample evidence that adrenal glucocorticoids mediate these effects of stress, the role of the sympatho-adrenal system in the effects of psychostimulants is poorly understood.

The Wobbler mouse spinal cord shows vacuolated motoneurons, glial reaction, inflammation and abnormal glutamatergic parameters. Wobblers also show deficits of motor performance. These conditions resemble amyotrophic lateral sclerosis (ALS). Wobbler mice also show high levels of corticosterone in blood, adrenals and brain plus adrenal hypertrophy, suggesting that chronically elevated glucocorticoids prime spinal cord neuroinflammation. Therefore, we analyzed if treatment of Wobbler mice with the glucocorticoid receptor (GR) antagonist CORT113176 mitigated the mentioned abnormalities. 30 mg/kg CORT113176 given daily for 3 weeks reduced motoneuron vacuolation, decreased astro and microgliosis, lowered the inflammatory mediators high mobility group box 1 protein (HMGB1), toll-like receptor 4, myeloid differentiation primary response 88 (MyD88), p50 subunit of nuclear factor kappa B (NFκB), tumor necrosis factor (TNF) receptor, and interleukin 18 (IL18) compared to untreated Wobblers. CORT113176 increased the survival signal pAKT (serine-threonine kinase) and decreased the death signal phosphorylated Junk-N-terminal kinase (pJNK), symptomatic of antiapoptosis. There was a moderate positive effect on glutamine synthase and astrocyte glutamate transporters, suggesting decreased glutamate excitotoxicity. In this pre-clinical study, Wobblers receiving CORT113176 showed enhanced resistance to fatigue in the rota rod test and lower forelimb atrophy at weeks 2-3. Therefore, long-term treatment with CORT113176 attenuated degeneration and inflammation, increased motor performance and decreased paw deformity. Antagonism of the GR may be of potential therapeutic value for neurodegenerative diseases.

Exposure to a chronic psychosocial stressor changes the behavioral and neuroendocrine response pattern and causes structural changes in the rodent hippocampus. However, the underlying molecular mechanism of these changes induced by chronic stress is largely unknown. Recently, it was shown that exposure to a dominant highly aggressive mouse in the sensory contact model induced long-lasting stress symptoms in subordinate mice genetically selected for long attack latency (LAL mice). The aim of the present study was to study the effect of chronic stress on hippocampal gene expression in these subordinate LAL mice. GeneChips (Affymetrix) were used to compare gene expression profiles of LAL mice exposed to a sensory contact stressor for 25 days and their controls (one array per mouse, n=5 per line). After this stress paradigm, 131 genes were found differentially expressed (P<0.01). Strikingly, all of these genes showed a subtle downregulation in response to a chronic stressor. Interestingly, a significant overrepresentation of genes encoding structural components of ribosomes were found, suggesting diminished protein biosynthesis in the hippocampus of chronically stressed LAL mice. In addition, several genes of the NFkappaB signaling cascade, a pathway crucially involved in neuronal viability and neurite growth, were found to be downregulated. Together, we hypothesize that reduced NFkappaB signaling and diminished protein biosynthesis form part of the molecular mechanisms by which a chronic psychosocial stressor induces structural alterations in hippocampus of LAL mice.

Dexamethasone (DEX), a synthetic glucocorticoid, has been used to treat respiratory distress syndrome in prematurely born infants. Despite the important short-term benefit on lung function, there is growing concern about the long-term outcome of this treatment, since follow-up studies of prematurely born infants have shown lasting adverse neurodevelopmental effects. Since the mechanism underlying these neurodevelopmental impairments is largely unknown, the aim of the present study was (i) to investigate the acute effects of neonatal DEX treatment on the developing brain; and (ii) to block specifically the effects of DEX on the brain by central administration of the glucocorticoid receptor (GR) antagonist mifepristone. Long Evans rat pups were injected subcutaneously with tapering doses of DEX or saline (SAL) on postnatal days (pnd) 1, 2 and 3. Separate groups received intracerebroventricular injections with mifepristone prior to DEX treatment. On pnd 4 and 10, pups were sacrificed and brains collected for analysis of cell proliferation (Ki-67) and astrogliosis (GFAP). We report that neonatal DEX treatment reduced hippocampal cell proliferation on pnd 4, an effect that was normalized by pnd 10. Although on pnd 4, GFAP expression was not affected, DEX treatment caused a significant reduction in the number and density of astrocytes in hippocampus and corpus callosum on pnd 10, which was normalized by mifepristone pre-treatment. These acute alterations in the neonate brain might underlie later functional impairments reported in DEX-treated animals and humans and further illustrate the impact of early GR activation on brain development.

In tauopathies, such as Alzheimer's disease with or without concomitant amyloid β plaques, cerebral arteries display pathological remodeling, leading to reduced brain tissue oxygenation and cognitive impairment. The precise mechanisms that underlie this vascular dysfunction remain unclear. Kv7 voltage-dependent K+ channels contribute to the development of myogenic tone in rat cerebral arteries. Thus, we hypothesized that Kv7 channel function would be impaired in the cerebral arteries of a tauopathy mouse model (rTg4510), which might underlie cerebral hypoperfusion associated with the development of neurofibrillary tangles in tauopathies. To test our hypothesis we performed wire myography and quantitative PCR on cerebral arteries, mesenteric arteries and the inferior frontotemporal region of the brain surrounding the middle cerebral artery from tau transgenic mice (rTg4510) and aged-matched controls. We also performed whole-cell patch clamp experiments on HEK293 cells stably expressing Kv7.4. Here, we show that Kv7 channels are functionally impaired in the cerebral arteries of rTg4510 mice, but not in mesenteric arteries from the same mice. The quantitative PCR analysis of the cerebral arteries found no change in the expression of the genes encoding the Kv7 channel α-subunits, however, we found reduced expression of the ancillary subunit, KCNE5 (also termed KCNE1L), in the cerebral arteries of rTg4510 mice. In the brain, rTg4510 mice showed reduced expression of Kv7.3, Kv7.5, and Kv2.1. Co-expression of KCNE5 with Kv7.4 in HEK293 cells produced larger currents at voltages >0 mV and increased the deactivation time for the Kv7.4 channel. Thus, our results demonstrate that Kv7 channel function is attenuated in the cerebral arteries of Tg4510 mice, which may result from decreased KCNE5 expression. Reduced Kv7 channel function might contribute to cerebral hypoperfusion in tauopathies, such as Alzheimer's disease.

Mitochondrial dysfunction was highlighted as a crucial vulnerability factor for the development of depression. However, systemic studies assessing stress-induced changes in mitochondria-associated genes in brain regions relevant to depression symptomatology remain scarce. Here, we performed a genome-wide transcriptomic study to examine mitochondrial gene expression in the prefrontal cortex (PFC) and nucleus accumbens (NAc) of mice exposed to multimodal chronic restraint stress. We identified mitochondria-associated gene pathways as most prominently affected in the PFC and with lesser significance in the NAc. A more detailed mitochondrial gene expression analysis revealed that in particular mitochondrial DNA-encoded subunits of the oxidative phosphorylation complexes were altered in the PFC. The comparison of our data with a reanalyzed transcriptome data set of chronic variable stress mice and major depression disorder subjects showed that the changes in mitochondrial DNA-encoded genes are a feature generalizing to other chronic stress-protocols as well and might have translational relevance. Finally, we provide evidence for changes in mitochondrial outputs in the PFC following chronic stress that are indicative of mitochondrial dysfunction. Collectively, our work reinforces the idea that changes in mitochondrial gene expression are key players in the prefrontal adaptations observed in individuals with high behavioral susceptibility and resilience to chronic stress.

Glucocorticoids exert antiinflammatory, antiproliferative and immunosupressive effects. Paradoxically they may also enhance inflammation particularly in the nervous system, as shown in Cushing´ syndrome and neurodegenerative disorders of humans and models of human diseases. ."The Wobbler mouse model of amyotrophic lateral sclerosis shows hypercorticoidism and neuroinflammation which subsided by treatment with the glucocorticoid receptor (GR) modulator Dazucorilant (CORT113176). This effect suggests that GR mediates the chronic glucocorticoid unwanted effects. We now tested this hypothesis using a chronic stress model resembling the condition of the Wobbler mouse Male NFR/NFR mice remained as controls or were subjected to a restraining / rotation stress protocol for 3 weeks, with a group of stressed mice receiving CORT113176 also for 3 weeks. We determined the mRNAS or reactive protein for the proinflamatory factors HMGB1, TLR4, NFkB, TNFα, markers of astrogliosis (GFAP, SOX9 and acquaporin 4), of microgliosis (Iba, CD11b, P2RY12 purinergic receptor) as well as serum IL1β and corticosterone. We showed that chronic stress produced high levels of serum corticosterone and IL1β, decreased body and spleen weight, produced microgliosis and astrogliosis and increased proinflammatory mediators. In stressed mice, modulation of the GR with CORT113176 reduced Iba + microgliosis, CD11b and P2RY12 mRNAs, immunoreactive HMGB1 + cells, GFAP + astrogliosis, SOX9 and acquaporin expression and TLR4 and NFkB mRNAs vs. stress-only mice. The effects of CORT113176 indicate that glucocorticoids are probably involved in neuroinflammation. Thus, modulation of the GR would become useful to dampen the inflammatory component of neurodegenerative disorders.

Attention deficit hyperactivity disorder (ADHD) is the most frequently diagnosed neurodevelopmental disorder worldwide. Affected individuals present with hyperactivity, inattention, and cognitive deficits and display a characteristic paradoxical response to drugs affecting the dopaminergic system. However, the underlying pathophysiology of ADHD and how this relates to dopaminergic transmission remains to be fully understood. Sorcs2-/- mice uniquely recapitulate symptoms reminiscent of ADHD in humans. Here, we show that lack of SorCS2 in mice results in lower sucrose intake, indicating general reward deficits. Using in-vivo recordings, we further find that dopaminergic transmission in the ventral tegmental area (VTA) is shifted towards a more regular firing pattern with marked reductions in the relative occurrence of irregular firing in Sorcs2-/- mice. This was paralleled by abnormal acute behavioral responses to dopamine receptor agonists, suggesting fundamental differences in dopaminergic circuits and indicating a perturbation in the balance between the activities of the postsynaptic dopamine receptor DRD1 and the presynaptic inhibitory autoreceptor DRD2. Interestingly, the hyperactivity and drug response of Sorcs2-/- mice were markedly affected by novelty. Taken together, our findings show how loss of a candidate ADHD-risk gene has marked effects on dopaminergic circuit function and the behavioral response to the environment.

It has been suggested that people with mental disorders have an elevated risk to acquire severe acute respiratory syndrome coronavirus 2 and to be disproportionally affected by coronavirus disease 19 (COVID-19) once infected. We aimed to analyse the COVID-19 infection rate, course and outcome, including mortality and long COVID, in people with anxiety, depressive, neurodevelopmental, schizophrenia spectrum and substance use disorders relative to control subjects without these disorders.