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Introduction
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Publications (85)
Most of the fear literature on humans and animals tests healthy individuals. However, fear memories can differ between healthy individuals and those previously exposed to traumatic stress, such as a car accident, sexual abuse, military combat and personal assault. Traumatic stress can lead to post-traumatic stress disorder (PTSD) which presents alt...
Exposure to traumatic stress can lead to fear dysregulation, which has been associated with posttraumatic stress disorder (PTSD). Previous work showed that a polymorphism in the PACAP-PAC1R (pituitary adenylate cyclase-activating polypeptide) system is associated with PTSD risk in women, and PACAP ( ADCYAP1 )-PAC1R ( ADCYAP1R1 ) are highly expresse...
Background:
Memory consolidation is a process required for the formation of long-term memories. The G-protein-coupled receptor (GPCR) neurokinin-3-receptor (Nk3R) and its interactions with sex hormones seem important for the modulation of fear memory consolidation: Nk3R antagonism in male mice impairs fear memory, but enhances it in females. Howev...
Memory formation is key for brain functioning. Uncovering the memory mechanisms is helping us to better understand neural processes in health and disease. Moreover, more specific treatments for fear-related disorders such as posttraumatic stress disorder and phobias may help to decrease their negative impact on mental health. In this line, the Tach...
We address some of the current limitations of translational research in fear memory and suggest alternatives that might help to overcome them. Appropriate fear responses are adaptive, but disruption of healthy fear memory circuits can lead to anxiety and fear-based disorders. Stress is one of the main environmental factors that can disrupt memory c...
Neural circuitry involved in anxiety and fear-related disorders exhibits strong sexual modulation. A limited number of studies integrating female and male data have revealed differences in neural networks, and distinct interconnectivity between these brain areas. Despite the efforts to incorporate female or mixed-sex data, there is compelling evide...
From pianist to pioneering neuroscientist, Dr. Raül Andero Galí brings a unique perspective to his role as ICREA (Institució Catalana de Recerca i Estudis Avançats) Research Professor at the Autonomous University of Barcelona (Universitat Autònoma de Barcelona). Following his PhD in Neuroscience, earning the Extraordinary Doctoral Prize, he worked...
In recent years, research has progressively increased the importance of considering sex differences in stress and fear memory studies. Many studies have traditionally focused on male subjects, potentially overlooking critical differences with females. Emerging evidence suggests that males and females can exhibit distinct behavioral and neurophysiol...
At the 39th meeting of the International Society of Traumatic Stress Studies, four leading scientists and clinicians were invited to reflect on their careers, focusing on the biological mechanisms and markers of traumatic stress. Dr. Raul Andero has contributed to understanding how stress alters memory networks in the brain, influencing the develop...
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. Optogenet...
With a total budget of €4,838,400, TOUCH (Towards the generation of excellent young doctoral researchers in inter-sectoral & transdisciplinary approach) will be able to bring on board 24 PhD students enrolled in a strategic UAB area: mental health and well-being.
The new programme involves several university departments, the CORE in Mental Health...
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 estrad...
Exposure to acute and chronic stress has a broad range of structural effects on the brain. The brain areas commonly targeted in the stress response models include the hippocampus, the amygdala, and the prefrontal cortex. Studies in patients suffering from the so-called stress-related disorders -embracing post-traumatic stress, major depressive and...
Fear extinction alterations are a core symptom of post-traumatic stress disorder(PTSD). Traditionally, animal models of fear extinction mainly use male subjects. Recently, more studies on fear extinction are including sex as a biological variable and thus also test females. We describe here how to induce impairments in fear extinction in both male...
Combining the use of ex vivo and in vivo optogenetics, viral tracing, electrophysiology and behavioral testing, we show that the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) gates anxiety-controlling circuits by differentially affecting synaptic efficacy at projections from the basolateral amygdala (BLA) to two different...
Restriction of free movement has historically been used as a model for inducing acute and chronic stress in laboratory animals. This paradigm is one of the most widely employed experimental procedures for basic research studies of stress-related disorders. It is easy to implement, and it rarely involves any physical harm to the animal. Many differe...
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...
Introduction
The incidence and severity of posttraumatic stress disorder (PTSD) is higher in women than men because of environmental and biological factors. Specific mechanisms in the PACAP-PAC1R (pituitary adenylate cyclase-activating polypeptide and its type I receptor) system may confer PTSD risk in women. Interestingly, while the PACAP ( ADCYAP...
Background
Pituitary adenylate cyclase-activating polypeptide (PACAP) receptor gene polymorphism has been postulated as a potential sex-specific diagnostic biomarker of trauma-related disorders. However, no research to date has evaluated whether the PACAPergic system may act as a vulnerability/resilience neuromechanism to trauma-induced psychopatho...
De novo protein synthesis is required for synapse modifications underlying stable memory encoding. Yet neurons are highly compartmentalized cells and how protein synthesis can be regulated at the synapse level is unknown. Here, we characterize neuronal signaling complexes formed by the postsynaptic scaffold GIT1, the mechanistic target of rapamycin...
Sexual assault is one of the most traumatic events a person can experience. Despite this, information regarding the risk factors associated with the development of Acute Stress Disorder (ASD) in sexual assault victims is scarce. A follow-up prospective cohort study was designed to examine the prevalence and risk factors of ASD in women exposed to a...
De novo protein synthesis is required for synapse modifications underlying stable memory encoding. Yet neurons are highly compartmentalized cells and how protein synthesis can be regulated at the synapse level is unknown. Here we characterize neuronal signaling complexes formed by the postsynaptic scaffold GIT1, the mTOR kinase and Raptor that coup...
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 severa...
Post-traumatic stress disorder (PTSD) is characterized by hypervigilance, increased reactivity to unpredictable versus predictable threat signals, deficits in fear extinction, and an inability to discriminate between threat and safety. First-line pharmacotherapies for psychiatric disorders have limited therapeutic efficacy in PTSD. However, recent...
Memory formation is key for brain functioning. Uncovering the memory mechanisms is helping us to better understand neural processes in health and disease. In this line, the Tachykinin 2 (Tac2) pathway in the central amygdala (CeA) has been shown to be sufficient and necessary for the modulation of fear memory consolidation. CeA-Tac2 antagonism and...
Memory formation is key for brain functioning. Uncovering the memory mechanisms is helping us to better understand neural processes in health and disease. Moreover, more specific treatments for fear-related disorders such as posttraumatic stress disorder and phobias may help to decrease their negative impact on mental health. In this line, the Tach...
Food addiction is linked to obesity and eating disorders and is characterized by a loss of behavioral control and compulsive food intake. Here, using a food addiction mouse model, we report that the lack of cannabinoid type-1 receptor in dorsal telencephalic glutamatergic neurons prevents the development of food addiction-like behavior, which is as...
Neuropeptide S (NPS) is a neuropeptide involved in the regulation of fear. Because safety learning is impaired in patients suffering from anxiety-related psychiatric disorders, and polymorphisms of the human neuropeptide S receptor (NPSR) gene have also been associated with anxiety disorders, we wanted to investigate whether NPSR-deficiency interfe...
Approximately one third of individuals who experience a severe traumatic event will develop posttraumatic stress disorder (PTSD). It is crucial to identify what factors may be associated with increased or decreased risk for PTSD. We conducted an umbrella review of systematic reviews and meta-analyses of risk/protective factors for PTSD and assessed...
Despite the exponential increase in fear research during the last years, few studies have included female subjects in their design. The need to include females arises from the knowledge gap of mechanistic processes underlying the behavioral and neural differences observed in fear extinction. Moreover, the exact contribution of sex and hormones in r...
In the last decade, previous studies have shown an increase in prolactin levels in drug-free patients with a first psychotic episode compared to healthy controls. Although pathophysiological mechanisms are not well understood, there is the possibility that this finding is secondary to the stressful context of the psychotic onset. Alternatively, pat...
Stress and trauma profoundly influence psychiatric biobehavioral outcomes. The identification of treatment and biomarker targets would be accelerated by a broad understanding of the biological responses to these events. The goal of this study was to determine genes responsive to auditory fear conditioning (FC), a well-characterized amygdala-depende...
Background:
Molecular mechanisms underlying psychological sequelae of exposure to stressful experiences, such as posttraumatic stress disorder (PTSD) and depression, are not well understood.
Methods:
Using convergent evidence from animal and human transcriptomic and genomic studies, we aimed to identify genetic mechanisms underlying depression a...
Despite extensive research on the impact of emotional stressors on brain function using immediate-early genes (e.g., c-fos), there are still important questions that remain unanswered such as the reason for the progressive decline of c-fos expression in response to prolonged stress and the neuronal populations activated by different stressors. This...
Recently we determined that activation of the Tachykinin 2 (Tac2) pathway in the central amygdala (CeA) is necessary and sufficient for the modulation of fear memories. The Tac2 pathway includes the Tac2 gene, which encodes the neuropeptide Neurokinin B and its corresponding receptor Neurokinin 3 receptor (NK3R). In this study, using Tac2-Cre and T...
Posttraumatic stress disorder (PTSD) it is both a prevalent and debilitating trauma-related disorder associated with dysregulated fear learning at the core of many of its signs and symptoms. Improvements in the currently available psychological and pharmacological treatments are needed in order to improve PTSD treatment outcomes and to prevent symp...
Acutely administered 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy') has been proposed to have long-term positive effects on post-traumatic stress disorder (PTSD) symptoms when combined with psychotherapy. No preclinical data support a mechanistic basis for these claims. Given the persistent nature of psychotherapeutic gains facilitated by MDMA...
Molecular Psychiatry publishes work aimed at elucidating biological mechanisms underlying psychiatric disorders and their treatment
In recent years, special attention is being paid to sex differences in susceptibility to disease. In this regard, there is evidence that male rats present higher levels of both cued and contextual fear conditioning than females. However, little is known about the concomitant hypothalamic-pituitary-adrenal (HPA) axis response to those situations whi...
Unlabelled:
Using an array-based approach after auditory fear conditioning and microRNA (miRNA) sponge-mediated inhibition, we identified a role for miR-34a within the basolateral amygdala (BLA) in fear memory consolidation. Luciferase assays and bioinformatics suggested the Notch pathway as a target of miR-34a. mRNA and protein levels of Notch re...
The centromedial amygdala (CeM), a subdivision of the central amygdala (CeA), is believed to be the main output station of the amygdala for fear expression. We provide evidence that the Tac2 gene, expressed by neurons specifically within the CeM, is required for modulating fear memories. Tac2 is colocalized with GAD65 and CaMKIIα but not with PKCd...
Brain-derived neurotrophic factor (BDNF) and its single transmembrane receptor, tropomysin-related kinase B (TrkB), are essential for adult synaptic plasticity and the formation of memories. However, there are regional and task-dependent differences underlying differential mechanisms of BDNF-TrkB function in the formation of these memories. Additio...
The amygdala-dependent molecular mechanisms driving the onset and persistence of posttraumatic stress disorder (PTSD) are poorly understood. Recent observational studies have suggested that opioid analgesia in the aftermath of trauma may decrease the development of PTSD. Using a mouse model of dysregulated fear, we found altered expression within t...
Brain-derived neurotrophic factor (BDNF) is the most studied neurotrophin involved in synaptic plasticity processes that are required for long-term learning and memory. Specifically, BDNF gene expression and activation of its high-affinity tropomyosin-related kinase B (TrkB) receptor are necessary in the amygdala, hippocampus and prefrontal cortex...
Post-traumatic stress disorder (PTSD) patients show cognitive deficits, but it is unclear whether these are a consequence of the pathology or a pre-existing factor of vulnerability to PTSD. Animal models may help to demonstrate whether or not exposure to certain stressors can actually induce long-lasting (LL; days) impairment of hippocampus-depende...
Despite increasing awareness of the many important roles played by brain-derived neurotrophic factor (BDNF) activation of TrkB, a fuller understanding of this system and the use of potential TrkB-acting therapeutic agents has been limited by the lack of any identified small-molecule TrkB agonists that fully mimic the actions of BDNF at brain TrkB r...
Chemical structures of gedunin derivatives. The first and last chemicals (beta-dihydrogedunol and alpha-dihydrogedunol) on the top row, the first one (dihydroxygedunol) in the middle row, and the third one on the bottom row (deoxygedunin) are the positive hits during cell-based screening and confirmed with primary cultures.
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Deoxygedunin is orally active and it does not regulate Trk receptor expression in mouse brain. (A) Two-three months old mice (C57BL/6J) mice were orally injected with various doses of 7,8-DHF or deoxygedunin. The mice were sacrificed 2 h or 4 h after drug administration. The brain lysates were prepared and analyzed by immunoblotting. TrkB in mouse...
Deoxygedunin displays potent therapeutic effects in cell death and stroke models. (A) Deoxygedunin decreases KA-induced apoptosis in mouse brain. The brain slides were analyzed with TUNEL assay. Green stands for apoptotic nuclei, which were also stained with DAPI; Kainic acid evidently initiated strong apoptosis in hippocampal CA3 region, which was...
Deoxygedunin is mainly concentrated in rat brain olfactory bulb and hippocampus. Two-three months old mice (C57BL/6J) mice were intraperitoneally injected with 30 µl of [3H]-deoxygedunin (2×106 cpm)/DMSO/PBS solution. In 4 h, various brain regions (A) and different organs (B) and were analyzed by liquid scintillation counter.
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Gedunin, a family of natural products from the Indian neem tree, possess a variety of biological activities. Here we report the discovery of deoxygedunin, which activates the mouse TrkB receptor and its downstream signaling cascades. Deoxygedunin is orally available and activates TrkB in mouse brain in a BDNF-independent way. Strikingly, it prevent...
Most drugs of abuse stimulate both locomotor activity and the hypothalamic-pituitary-adrenal (HPA) axis, but the relationship between the two responses within the same subjects and their reliabilities has been scarcely studied. Our objectives were to study: (1) the consistency and stability across time of locomotor and HPA activation induced by rep...
Exposure of rodents to cats or certain cat odors results in long-term behavioral effects reminiscent of enhanced anxiety that have been considered to model post-traumatic stress disorder. However, other severe stressors such as tail-shock or immobilization in wooden boards (IMO) appear to induce shorter lasting changes in anxiety. In addition, ther...
The pedunculopontine tegmental nucleus (PPTg) is involved in the regulation of thalamocortical transmission and of several functions related to ventral and dorsal striatal circuits. Stimulation of the PPTg in anesthetized animals increases cortical arousal, cortical acetylcholine release, bursting activity of mesopontine dopaminergic cells, and str...
