In the recent decade, fear conditioning has evolved as a standard procedure for testing cognitive abilities such as memory acquisition, consolidation, recall, reconsolidation, and extinction, ...preferentially in genetically modified mice. The reasons for the popularity of this powerful approach are its ease to perform, the short duration of training and testing, and its well-described neural basis. So why to bother about flaws in standardization of test procedures and analytical routines? Simplicity does not preclude the existence of fallacies. A short survey of the literature revealed an indifferent use of acoustic stimuli in terms of quality (i.e., white noise vs. sine wave), duration, and intensity. The same applies to the shock procedures. In the present article, I will provide evidence for the importance of qualitative and quantitative parameters of conditioned and unconditioned stimuli for the experimental outcome. Moreover, I will challenge frequently applied interpretations of short-term vs. long-term extinction and spontaneous recovery. On the basis of these concerns, I suggest a guideline for standardization of fear conditioning experiments in mice to improve the comparability of the experimental data.
Balanced control of neuronal activity is central in maintaining function and viability of neuronal circuits. The endocannabinoid system tightly controls neuronal excitability. Here, we show that ...endocannabinoids directly target hippocampal glutamatergic neurons to provide protection against acute epileptiform seizures in mice. Functional CB1 cannabinoid receptors are present on glutamatergic terminals of the hippocampal formation, colocalizing with vesicular glutamate transporter 1 (VGluT1). Conditional deletion of the
CB1 gene either in cortical glutamatergic neurons or in forebrain GABAergic neurons, as well as virally induced deletion of the
CB1 gene in the hippocampus, demonstrate that the presence of CB1 receptors in glutamatergic hippocampal neurons is both necessary and sufficient to provide substantial endogenous protection against kainic acid (KA)-induced seizures. The direct endocannabinoid-mediated control of hippocampal glutamatergic neurotransmission may constitute a promising therapeutic target for the treatment of disorders associated with excessive excitatory neuronal activity.
N6-methyladenosine (m6A) and N6,2′-O-dimethyladenosine (m6Am) are abundant mRNA modifications that regulate transcript processing and translation. The role of both, here termed m6A/m, in the stress ...response in the adult brain in vivo is currently unknown. Here, we provide a detailed analysis of the stress epitranscriptome using m6A/m-seq, global and gene-specific m6A/m measurements. We show that stress exposure and glucocorticoids region and time specifically alter m6A/m and its regulatory network. We demonstrate that deletion of the methyltransferase Mettl3 or the demethylase Fto in adult neurons alters the m6A/m epitranscriptome, increases fear memory, and changes the transcriptome response to fear and synaptic plasticity. Moreover, we report that regulation of m6A/m is impaired in major depressive disorder patients following glucocorticoid stimulation. Our findings indicate that brain m6A/m represents a novel layer of complexity in gene expression regulation after stress and that dysregulation of the m6A/m response may contribute to the pathophysiology of stress-related psychiatric disorders.
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•m6A/m mRNA methylation in the adult mouse brain is regulated by stress•m6A/m mRNA regulation is brain region, time, and gene specific•Mettl3 and Fto cKO alter m6A/m, fear memory, expression, and synaptic plasticity•The m6A/m glucocorticoid response is impaired in major depressive disorder patients
Engel et al. demonstrate a region- and time-dependent role of brain m6A/m methylation in stress-response regulation. Manipulating m6A/m alters fear memory, transcriptome response, and synaptic plasticity. Altered m6A/m dynamics in depressed patients suggest importance of m6A/m modifications for stress-related psychiatric disorders.
The endocannabinoid system (ECS), comprising two G protein-coupled receptors (the cannabinoid receptors 1 and 2 CB1 and CB2 for marijuana's psychoactive principle ∆(9)-tetrahydrocannabinol ∆(9)-THC), ...their endogenous small lipid ligands (namely anandamide AEA and 2-arachidonoylglycerol 2-AG, also known as endocannabinoids), and the proteins for endocannabinoid biosynthesis and degradation, has been suggested as a pro-homeostatic and pleiotropic signaling system activated in a time- and tissue-specific way during physiopathological conditions. In the brain activation of this system modulates the release of excitatory and inhibitory neurotransmitters and of cytokines from glial cells. As such, the ECS is strongly involved in neuropsychiatric disorders, particularly in affective disturbances such as anxiety and depression. It has been proposed that synthetic molecules that inhibit endocannabinoid degradation can exploit the selectivity of endocannabinoid action, thus activating cannabinoid receptors only in those tissues where there is perturbed endocannabinoid turnover due to the disorder, and avoiding the potential side effects of direct CB1 and CB2 activation. However, the realization that endocannabinoids, and AEA in particular, also act at other molecular targets, and that these mediators can be deactivated by redundant pathways, has recently led to question the efficacy of such approach, thus opening the way to new multi-target therapeutic strategies, and to the use of non-psychotropic cannabinoids, such as cannabidiol (CBD), which act via several parallel mechanisms, including indirect interactions with the ECS. The state of the art of the possible therapeutic use of endocannabinoid deactivation inhibitors and phytocannabinoids in mood disorders is discussed in this review article.
Recent findings obtained in patients with phobias or trauma-related anxiety disorders raise doubts concerning the interrelation between acute fear relief during an exposure-based therapeutic session ...and beneficial treatment progress. In a mouse model explicit for exposure therapy, we challenge the view that within-session fear reduction is the turning point for relearning of a stimulus-threat association. Even though within-session extinction of auditory-cued fear memory was identical for prolonged and spaced tone presentations, only the latter caused between-session extinction. Furthermore, spaced tone presentations led to between-session extinction even in the complete absence of within-session extinction, as observed for remote fear memories and in case of abolished cannabinoid receptor type 1 signaling. Induction of between-session extinction was accompanied by an increase in the number of c-Fos-positive neurons within the basolateral amygdala, the cingulate cortex, and the dentate gyrus, independent of the level of within-session extinction. Together, our findings demonstrate that within-session extinction is neither sufficient nor essential for between-session extinction, thus calling for a reconsideration of current concepts underlying exposure-based therapies.
•We highlight components of the eCB system that offer potential ‘druggable’ targets for new anxiolytic medications.•Amplifying eCBs by attenuating eCB-degradation, via fatty acid amide hydrolyze or ...monoacylglycerol lipase, reduces anxiety.•A non-canonical route to regulate eCB degradation and anxiety involves interfering with cyclooxygenase-2 (COX-2).•Anxiety can be affected by targeting the CB2R subtype and the transient receptor potential vanilloid receptor type 1 (TRPV1).•Cannabidiol (CBD) represents another plausible path to modulating eCBs to alleviate anxiety.
The endocannabinoid (eCB) system has attracted attention for its role in various behavioral and brain functions, and as a therapeutic target in neuropsychiatric disease states, including anxiety disorders and other conditions resulting from dysfunctional responses to stress. In this mini-review, we highlight components of the eCB system that offer potential ‘druggable’ targets for new anxiolytic medications, emphasizing some of the less well-discussed options. We discuss how selectively amplifying eCBs recruitment by interfering with eCB-degradation, via fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), has been linked to reductions in anxiety-like behaviors in rodents and variation in human anxiety symptoms. We also discuss a non-canonical route to regulate eCB degradation that involves interfering with cyclooxygenase-2 (COX-2). Next, we discuss approaches to targeting eCB receptor-signaling in ways that do not involve the cannabinoid receptor subtype 1 (CB1R); by targeting the CB2R subtype and the transient receptor potential vanilloid type 1 (TRPV1). Finally, we review evidence that cannabidiol (CBD), while representing a less specific pharmacological approach, may be another way to modulate eCBs and interacting neurotransmitter systems to alleviate anxiety. Taken together, these various approaches provide a range of plausible paths to developing novel compounds that could prove useful for treating trauma-related and anxiety disorders.
The recent shift in socio-political debates and growing liberalization of Cannabis use across the globe has raised concern regarding its impact on vulnerable populations such as adolescents. ...Concurrent with declining perception of Cannabis harms, more adolescents are using it daily in several countries and consuming marijuana strains with high content of psychotropic delta (9)-tetrahydrocannabinol (THC). These dual, related trends seem to facilitate the development of compromised social and cognitive performance at adulthood, which are described in preclinical and human studies. Cannabis exerts its effects via altering signalling within the endocannabinoid system (ECS), which modulates the stress circuitry during the neurodevelopment. In this context early interventions appear to circumvent the emergence of adult neurodevelopmental deficits. Accordingly, Cannabis sativa second-most abundant compound, cannabidiol (CBD), emerges as a potential therapeutic agent to treat neuropsychiatric disorders. We first focus on human and preclinical studies on the long-term effects induced by adolescent THC exposure as a “critical window” of enhanced neurophysiological vulnerability, which could be involved in the pathophysiology of schizophrenia and related primary psychotic disorders. Then, we focus on adolescence as a “window of opportunity” for early pharmacological treatment, as novel risk reduction strategy for neurodevelopmental disorders. Thus, we review current preclinical and clinical evidence regarding the efficacy of CBD in terms of positive, negative and cognitive symptoms treatment, safety profile, and molecular targets.
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Adverse early life events can induce long-lasting changes in physiology and behavior. We found that early-life stress (ELS) in mice caused enduring hypersecretion of corticosterone and alterations in ...passive stress coping and memory. This phenotype was accompanied by a persistent increase in arginine vasopressin (AVP) expression in neurons of the hypothalamic paraventricular nucleus and was reversed by an AVP receptor antagonist. Altered Avp expression was associated with sustained DNA hypomethylation of an important regulatory region that resisted age-related drifts in methylation and centered on those CpG residues that serve as DNA-binding sites for the methyl CpG-binding protein 2 (MeCP2). We found that neuronal activity controlled the ability of MeCP2 to regulate activity-dependent transcription of the Avp gene and induced epigenetic marking. Thus, ELS can dynamically control DNA methylation in postmitotic neurons to generate stable changes in Avp expression that trigger neuroendocrine and behavioral alterations that are frequent features in depression.
: Posttraumatic stress disorder (PTSD) belongs to the most frequent anxiety disorders. Despite a broad body of evidence concerning neurobiological correlates of this illness, the pathomechanisms of ...PTSD are still poorly understood. This illustrates the need to establish animal models of this disorder. Recently, PTSD model has become a somewhat fashionable term used in animal studies for almost every stress‐induced behavioral alteration. Only few cases, however, reflect the human disorder closely enough to deserve this term. Systematic research requires valid animal modeling with clearly defined criteria. This article outlines and discusses criteria for prospective PTSD models, based on a theoretical framework that emphasizes the involvement of both associative and nonassociative memory processes in the development and maintenance of PTSD.
The recently proposed Research Domain Criteria (RDoC) system defines psychopathologies as phenomena of multilevel neurobiological existence and assigns them to 5 behavioural domains characterizing a ...brain in action. We performed an analysis on this contemporary concept of psychopathologies in respect to a brain phylogeny and biological substrates of psychiatric diseases. We found that the RDoC system uses biological determinism to explain the pathogenesis of distinct psychiatric symptoms and emphasises exploration of endophenotypes but not of complex diseases. Therefore, as a possible framework for experimental studies it allows one to evade a major challenge of translational studies of strict disease-to-model correspondence. The system conforms with the concept of a normality and pathology continuum, therefore, supports basic studies. The units of analysis of the RDoC system appear as a novel matrix for model validation. The general regulation and arousal, positive valence, negative valence, and social interactions behavioural domains of the RDoC system show basic construct, network, and phenomenological homologies between human and experimental animals. The nature and complexity of the cognitive behavioural domain of the RDoC system deserve further clarification. These homologies in the 4 domains justifies the validity, reliably and translatability of animal models appearing as endophenotypes of the negative and positive affect, social interaction and general regulation and arousal systems’ dysfunction.
•The RDoC system encourages endophenotype-oriented experimental studies in human and animals.•The system conforms with the normality-pathology continuum concept.•The RDoC system appears to be a suitable framework for basic research.•Four RDoC domains show construct and phenomenological homology in human and animals.•Endophenotype-based models of affective psychopathologies appear most reliable.