Activation of AMPA Receptors Mediates the Antidepressant Action of Deep Brain Stimulation of the Infralimbic Prefrontal Cortex.

Although deep brain stimulation (DBS) has been used with success in treatment-resistant depression, little is known about its mechanism of action. We examined the antidepressant-like activity of short (1 h) DBS applied to the infralimbic prefrontal cortex in the forced swim test (FST) and the novelty-suppressed feeding test (NSFT). We also used in vivo microdialysis to evaluate the release of glutamate, γ-aminobutyric acid, serotonin, dopamine, and noradrenaline in the prefrontal cortex and c-Fos immunohistochemistry to determine the brain regions activated by DBS. One hour of DBS of the infralimbic prefrontal cortex has antidepressant-like effects in FST and NSFT, and increases prefrontal efflux of glutamate, which would activate AMPA receptors (AMPARs). This effect is specific of the infralimbic area since it is not observed after DBS of the prelimbic subregion. The activation of prefrontal AMPARs would result in a stimulation of prefrontal output to the brainstem, thus increasing serotonin, dopamine, and noradrenaline in the prefrontal cortex. Further, the activation of prefrontal AMPARs is necessary and sufficient condition for the antidepressant response of 1 h DBS.

Corticosterone administration immediately after peripuberty stress exposure does not prevent protracted stress-induced behavioral alterations.

Stress-related disorders are commonly associated with abnormalities in hypothalamic-pituitary-adrenal (HPA) axis activity. Preliminary studies with cortisol administration in the aftermath of trauma suggest that this HPA axis hormone can potentially prevent maladaptive behavioral and biological stress responses. However, the efficacy of glucocorticoid administration during the peripuberty period has not been tested yet, although this lifetime is a critical time window in brain development and is highly sensitive to the harmful effects of stress. To further examine the short and long-lasting impact of glucocorticoids treatment given during the post-peripubertal stress period, the present study utilized a rat model of peripubertal stress-induced psychopathology and animals were subjected to a battery of tests to assess anxiety-like behaviors, exploratory behavior and reactivity to novelty at late adolescence and sociability, anhedonia and stress coping behaviors at adulthood. All the experiments were performed in males and females to evaluate the potential behavioral sex differences. Overall, our results demonstrated that rats exposed to peripubertal stress show decreased sociability in adulthood without differences in anxiety and depression-like behaviors. Moreover, this study shows that the administration of corticosterone after stress exposure at peripuberty does not prevent stress-induced behavioral alterations. However, we observed that some stress-induced behavioural alterations and corticosterone responses are sex-specific. Thus, the data obtained highlight that delineating sex differences in stress-related studies may ultimately contribute to the development of effective therapeutic interventions for each sex.

Sex differences in neural projections of fear memory processing in mice and humans.

It remains unexplored in the field of fear memory whether functional neuronal connectivity between two brain areas is necessary for one sex but not the other. Here, we show that chemogenetic silencing of centromedial (CeM)-Tac2 fibers in the lateral posterior BNST (BNSTpl) decreased fear memory consolidation in male mice but not females. Optogenetic excitation of CeM-Tac2 fibers in the BNSTpl exhibited enhanced inhibitory postsynaptic currents in males compared to females. In vivo calcium imaging analysis revealed a sex-dimorphic fear memory engram in the BNSTpl. Furthermore, in humans, the single-nucleotide polymorphism (SNP) in the Tac2 receptor (rs2765) (TAC3R) decreased CeM-BNST connectivity in a fear task, impaired fear memory consolidation, and increased the expression of the TAC3R mRNA in AA-carrier men but not in women. These sex differences in critical neuronal circuits underlying fear memory formation may be relevant to human neuropsychiatric disorders with fear memory alterations such as posttraumatic stress disorder.

The Impacts of Sex Differences and Sex Hormones on Fear Extinction.

Fear extinction memories are strongly modulated by sex and hormonal status, but the exact mechanisms are still being discovered. In humans, there are some basal and task-related features in which male and female individuals differ in fear conditioning paradigms. However, analyses considering the effects of sex hormones demonstrate a role for estradiol in fear extinction memory consolidation. Translational studies are taking advantage of the convergent findings between species to understand the brain structures implicated. Nevertheless, the human brain is complex and the transfer of these findings into the clinics remains a challenge. The promising advances in the field together with the standardization of fear extinction methodologies in humans will benefit the design of new personalized therapies.

Glucocorticoid-based pharmacotherapies preventing PTSD.

Posttraumatic stress disorder (PTSD) is a highly disabling psychiatric condition that may arise after exposure to acute and severe trauma. It is a highly prevalent mental disorder worldwide, and the current treatment options for these patients remain limited due to low effectiveness. The time window right after traumatic events provides clinicians with a unique opportunity for preventive interventions against potential deleterious alterations in brain function that lead to PTSD. Some studies pointed out that PTSD patients present an abnormal function of the hypothalamic-pituitary-adrenal axis that may contribute to a vulnerability toward PTSD. Moreover, glucocorticoids have arisen as a promising option for preventing the disorder's development when administered in the aftermath of trauma. The present work compiles the recent findings of glucocorticoid administration for the prevention of a PTSD phenotype, from human studies to animal models of PTSD. Overall, glucocorticoid-based therapies for preventing PTSD demonstrated moderate evidence in terms of efficacy in both clinical and preclinical studies. Although clinical studies point out that glucocorticoids may not be effective for all patients' subpopulations, those with adequate traits might greatly benefit from them. Preclinical studies provide precise insight into the mechanisms mediating this preventive effect, showing glucocorticoid-based prevention to reduce long-lasting behavioral and neurobiological abnormalities caused by traumatic stress. However, further research is needed to delineate the precise mechanisms and the extent to which these interventions can translate into lower PTSD rates and morbidity. This article is part of the Special Issue on 'Fear, Anxiety and PTSD'.

Developing the next generation of renewable energy technologies: an overview of low-TRL EU-funded research projects.

A cluster of eleven research and innovation projects, funded under the same call of the EU's H2020 programme, are developing breakthrough and game-changing renewable energy technologies that will form the backbone of the energy system by 2030 and 2050 are, at present, at an early stage of development. These projects have joined forces at a collaborative workshop, entitled ' Low-TRL Renewable Energy Technologies', at the 10th Sustainable Places Conference (SP2022), to share their insights, present their projects' progress and achievements to date, and expose their approach for exploitation and market uptake of their solutions.

Direct and Indirect Measurements of Sex Hormones in Rodents During Fear Conditioning.

Fear conditioning (FC) is a widely accepted tool for the assessment of learning and memory processes in rodents related to normal and dysregulated acquired fear. The study of sex differences in fear learning and memory is vast and currently increasing. Sex hormones have proven to be crucial for fear memory formation in males and females, and several methods have been developed to assess this hormonal state in rats and mice. Herein, we explain a routine FC and extinction protocol, together with the evaluation of sex hormonal state in male and female rodents. We explain three protocols for the evaluation of this hormonal state directly from blood samples extracted during the procedure or indirectly through histological verification of the estrous cycle for females or behavioral assessment of social hierarchies in males. Although females have typically been considered to present great variability in sex hormones, it is highlighted that sex hormone assessment in males is as variable as in females and equally important for fear memory formation. The readout of these protocols has had a great impact on different fields of fear learning and memory study and appears essential when studying FC. The proven interaction with drugs involved in the modulation of these processes makes sex hormone assessment during FC a valuable tool for the development of effective treatments for fear-related disorders in men and women. © 2021 Wiley Periodicals LLC. Basic Protocol 1: Fear conditioning and fear extinction Basic Protocol 2: Blood collection for direct measurement of sex hormone levels in fear conditioning Basic Protocol 3: Indirect measurement of sex hormones in females during fear conditioning Basic Protocol 4: Assessment of dominance status in males before a fear conditioning protocol Support Protocol: Construction of a confrontation tube.

Induced Dipoles and Possible Modulation of Wireless Effects in Implanted Electrodes. Effects of Implanting Insulated Electrodes on an Animal Test to Screen Antidepressant Activity.

There is evidence that Deep Brain Stimulation (DBS) produces health benefits in patients even before initiating stimulation. Furthermore, DBS electrode insertion in rat infralimbic cortex (ILC) provokes antidepressant-like effects before stimulation, due to local inflammation and astrogliosis. Consequently, a significant effect of implanting electrodes is suspected. External fields, similar in magnitude to the brain's endogenous fields, induce electric dipoles in conducting materials, in turn influencing neural cell growth through wireless effects. To elucidate if such dipoles influence depressive-like behavior, without external stimulation, the comparative effect of conducting and insulated electrodes along with the glial response is studied in unstressed rats. Naïve and implanted rats with electrically insulated or uninsulated steel electrodes were evaluated in the modified forced swimming test and expression of ILC-glial markers was assessed. An antidepressant-like effect was observed with conducting but not with insulated electrodes. Gliosis was detected in both groups, but astroglial reactivity was larger near uninsulated electrodes. Thus, induced dipoles and antidepressant-like effects were only observed with conducting implants. Such correlation suggests that dipoles induced in electrodes by endogenous fields in turn induce neuron stimulation in a feedback loop between electrodes and neural system. Further research of the effects of unwired conducting implants could open new approaches to regulating neuronal function, and possibly treat neurological disorders.

Ketamine promotes rapid and transient activation of AMPA receptor-mediated synaptic transmission in the dorsal raphe nucleus.

Accumulating evidence indicates that the antidepressant effects of ketamine are, in part, mediated by an increase in the AMPA receptor-mediated neurotransmission in depression related areas, such as the prefrontal cortex (PFC). Therefore, activity in PFC-projecting areas related to major depression, such as the dorsal raphe nucleus (DR), may also be modulated by ketamine. We used whole-cell patch-clamp recordings and western blot experiments to determine whether ketamine promotes acute and maintained alterations in glutamatergic transmission and mTOR pathway in the DR. Bath perfusion of ketamine, but not the NMDA receptor antagonist D-AP5, increased the frequency of AMPA receptor-mediated spontaneous EPSCs (sEPSCs) in DR neurons. However, ketamine did not affect evoked EPSCs or spontaneous inhibitory currents (sIPSCs). Pre-incubation of DR slices with the mTOR inhibitor PP242 decreased the frequency of sEPSCs and prevented the effect of ketamine. The results also show that while no electrophysiological effects were detected 24 h after ketamine administration, phosphorylation levels of mTOR were significantly increased in the DR. Nevertheless, expression levels of synaptic proteins were unaffected at that time. Altogether, the present data demonstrate that ketamine transiently increases spontaneous AMPA receptor-mediated neurotransmission in the DR.

Risperidone administered during adolescence induced metabolic, anatomical and inflammatory/oxidative changes in adult brain: A PET and MRI study in the maternal immune stimulation animal model.

Inflammation and oxidative stress (IOS) are considered key pathophysiological elements in the development of mental disorders. Recent studies demonstrated that the antipsychotic risperidone elicits an antiinflammatory effect in the brain. We administered risperidone for 2-weeks at adolescence to assess its role in preventing brain-related IOS changes in the maternal immune stimulation (MIS) model at adulthood. We also investigated the development of volumetric and neurotrophic abnormalities in areas related to the HPA-axis. Poly I:C (MIS) or saline (Sal) were injected into pregnant Wistar rats on GD15. Male offspring received risperidone or vehicle daily from PND35-PND49. We studied 4 groups (8-15 animals/group): Sal-vehicle, MIS-vehicle, Sal-risperidone and MIS-risperidone. [18F]FDG-PET and MRI studies were performed at adulthood and analyzed using SPM12 software. IOS and neurotrophic markers were measured using WB and ELISA assays in brain tissue. Risperidone elicited a protective function of schizophrenia-related IOS deficits. In particular, risperidone elicited the following effects: reduced volume in the ventricles and the pituitary gland; reduced glucose metabolism in the cerebellum, periaqueductal gray matter, and parietal cortex; higher FDG uptake in the cingulate cortex, hippocampus, thalamus, and brainstem; reduced NFκB activity and iNOS expression; and increased enzymatic activity of CAT and SOD in some brain areas. Our study suggests that some schizophrenia-related IOS changes can be prevented in the MIS model. It also stresses the need to search for novel strategies based on anti-inflammatory compounds in risk populations at early stages in order to alter the course of the disease.

Effect of Deep Brain Stimulation of the ventromedial prefrontal cortex on the noradrenergic system in rats.

BACKGROUND: Deep Brain Stimulation (DBS) of the subgenual cingulate cortex (SCC) is a promising therapeutic alternative to treat resistant major depressive disorder. In preclinical studies, DBS of the ventromedial prefrontal cortex (vmPFC, the rodent SCC correlate) provokes an antidepressant-like effect, along with changes in noradrenaline levels at the site of stimulation. Hence, DBS appears to activate the noradrenergic-locus coeruleus (LC) system. OBJECTIVE/HYPOTHESIS: The aim of this study was to evaluate the effect of vmPFC DBS on the electrical activity of noradrenergic LC neurons, cortical oscillations and coherence between both brain areas in male rats. METHODS: The antidepressant-like effect of vmPFC DBS was evaluated through the forced swimming test. Tonic and evoked activity of LC neurons, LC activity of alpha2-adrenoceptors, local field potentials from LC and electrocorticogram signals were studied after DBS by electrophysiological recordings in anaesthetized rats. The effect of DBS on tyrosine hydroxylase (TH), noradrenaline transporters (NAT), phosphorylation of the extracellular signal-regulated kinase (ERK) and corticotropin releasing factor (CRF) expression in the LC were measured by western blot assays. RESULTS: DBS induced an antidepressant-like effect increasing climbing behaviour in the FST that was accompanied by a robust increase of TH expression in the rat LC. The tonic and evoked activity of LC neurons was enhanced by DBS, which impaired alpha2-adrenoceptors activity. DBS also promoted an increase in slow LC oscillations, as well as a shift in LC-cortical coherence. CONCLUSION: DBS of the vmPFC appears to affect the LC, producing changes that may underlie its antidepressant-like effects.

Fluoxetine: a case history of its discovery and preclinical development.

INTRODUCTION: Depression is a multifactorial mood disorder with a high prevalence worldwide. Until now, treatments for depression have focused on the inhibition of monoaminergic reuptake sites, which augment the bioavailability of monoamines in the CNS. Advances in drug discovery have widened the therapeutic options with the synthesis of so-called selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine. AREAS COVERED: The aim of this case history is to describe and discuss the pharmacokinetic and pharmacodynamic profiles of fluoxetine, including its acute effects and the adaptive changes induced after long-term treatment. Furthermore, the authors review the effect of fluoxetine on neuroplasticity and adult neurogenesis. In addition, the article summarises the preclinical behavioural data available on fluoxetine's effects on depressive-like behaviour, anxiety and cognition as well as its effects on other diseases. Finally, the article describes the seminal studies validating the antidepressant effects of fluoxetine. EXPERT OPINION: Fluoxetine is the first selective SSRI that has a recognised clinical efficacy and safety profile. Since its discovery, other molecules that mimic its mechanism of action have been developed, commencing a new age in the treatment of depression. Fluoxetine has also demonstrated utility in the treatment of other disorders for which its prescription has now been approved.

Efficacy and tolerability of telaprevir (TVR)-based triple therapy in HIV/HCV-coinfected patients.

INTRODUCTION: Clinical trials (CT) on triple therapy against HCV infection in HIV-infected patients including TVR plus pegylated interferon and ribavirin (PR) have reported considerably higher response rates than with PR alone. This study was aimed to evaluate the efficacy and safety of triple therapy including TVR in HIV/HCV-coinfected patients in real-life conditions. MATERIALS AND METHODS: HIV/HCV genotype 1 patients seen at four Hospitals in Madrid who received therapy including TVR plus PR for at least two weeks were included. The response was evaluated during treatment, and sustained viral response (SVR) was evaluated 12 and 24 weeks after the end of the treatment. RESULTS: Fifty-eight patients have been included; 79% male, median age 48 y.o.; 38% were IL28B rs12979860 genotype CT or TT, 58.6% of patients presented cirrhosis and 24.1% presented fibrosis F3. Infection with genotype 1a was observed in 53.4% of patients. Median baseline HCV-RNA was 3,282,263 IU/mL (77.5% had >800,000 IU/mL). The most commonly used antiretroviral (ARV) drugs were tenofovir/emtricitabine [36 (62%) patients], etravirine [21 (36%) patients], abacavir/lamivudine [18 (31%) patients], boosted protease inhibitors [16 (27.5%) patients] and raltegravir [12 (20.6%) patients]. Of the 42 (72.4%) patients who had received previous HCV treatment, 13.7% were null responders, 25.8% were partial responders and 31% had relapsed. In an ITT approach, proportions of patients with undetectable HCV RNA were 67.8% (38/56) at TW4, 83.3% (40/48) at TW12, 80% (36/45) at TW24, 79.4% at TW36 (31/39) and 72% (26/36) at TW48. Fifteen (25.8%) patients discontinued HCV therapy [8 (13.8%) because they fulfilled stopping rules, 5 (8.6%) individuals due to adverse events and 2 (3.4%) were lost to follow-up]. Rash associated with TVR (grade 1) was observed in two cases (3.4%) and all the patients showed anaemia at some point of treatment. In an analysis by ITT in the 31 patients who had a 60 week follow-up after starting therapy, SVR-12 was observed in 21 (67.7%) patients. And in the analysis by ITT in 28 patients who had a 72 week follow-up after starting therapy, SVR-24 was observed in 17 (60.7%) patients. CONCLUSIONS: Response to triple therapy with TVR plus PR in HIV/HCV-patients under real-life conditions, and therefore, including a high proportion of difficult to treat patients, is similar to that found in CT. The safety profile of TVR-based therapy is also comparable to that shown in CT, with only a rate of discontinuation of 8.6% of individuals related to toxicity.

Preclinical discovery of duloxetine for the treatment of depression.

INTRODUCTION: Affective disorders, including major depressive disorder (MDD), are among the most severely disabling mental disorders, and in many cases are associated with poor treatment outcomes. From the emergence of the monoamine hypothesis of depression, the first-line treatment for MDD had mainly acted by inhibiting monoamine reuptake, and thereby increasing these levels in the synaptic cleft. However, in recent years, several new antidepressant drugs have appeared, including duloxetine, a dual serotonin (5-HT) and noradrenaline (NA) reuptake inhibitor recommended for the treatment of MDD. AREAS COVERED: The article reviews and discusses the biochemical and functional profile of duloxetine splitting the review into acute and long-term treatment with this dual monoamine reuptake inhibitor. In addition, the authors summarize available preclinical behavioral research data, which have demonstrated among other effects, the antidepressant-like activity of duloxetine in several animal models. The authors focus on the most recent literature on synaptic neuroplasticity modulation of this antidepressant drug. Finally, the authors briefly mention other approved indications of duloxetine. EXPERT OPINION: Duloxetine inhibits 5-HT and NA reuptake, effectively desensitizes various autoreceptors and promotes neuroplasticity. Clinically, duloxetine is an effective antidepressant that is well tolerated and has significant efficacy in the treatment of MDD.