Orexin mechanisms in the prelimbic cortex modulate the expression of contextual conditioned fear.

Rationale: Despite the existing anatomical and physiological evidence pointing to the involvement of orexinergic projections from the lateral hypothalamus (LH) in regulating fear-related responses, little is known regarding the contribution of the orexin system in the prelimbic cortex (PL) on contextual fear.

Objectives: We investigated the role of orexin-A (Orx) and orexin type 1 receptors (OrxR) in the PL during the expression of contextual conditioned fear in mice.

Methods: Neural tract tracing of the LH-PL pathway and OrxR immunoreactivity in the PL of C57BL/6 male mice were performed.

Kappa-opioid receptor blockade in the inferior colliculus of prey threatened by pit vipers decreases anxiety and panic-like behaviour.

The dorsal midbrain comprises dorsal columns of the periaqueductal grey matter and corpora quadrigemina. These structures are rich in beta-endorphinergic and leu-enkephalinergic neurons and receive GABAergic inputs from substantia nigra pars reticulata. Although the inferior colliculus (IC) is mainly involved in the acoustic pathways, the electrical and chemical stimulation of central and pericentral nuclei of the IC elicits a vigorous defensive behaviour.

Inhibiting Hippo pathway kinases releases WWC1 to promote AMPAR-dependent synaptic plasticity and long-term memory in mice.

The localization, number, and function of postsynaptic AMPA-type glutamate receptors (AMPARs) are crucial for synaptic plasticity, a cellular correlate for learning and memory. The Hippo pathway member WWC1 is an important component of AMPAR-containing protein complexes. However, the availability of WWC1 is constrained by its interaction with the Hippo pathway kinases LATS1 and LATS2 (LATS1/2).

Long-term adaptation of prefrontal circuits in a mouse model of NMDAR hypofunction.

Pharmacological approaches to induce N-methyl-d-aspartate receptor (NMDAR) hypofunction have been intensively used to understand the aetiology and pathophysiology of schizophrenia. Yet, the precise cellular and molecular mechanisms that relate to brain network dysfunction remain largely unknown. Here, we used a set of complementary approaches to assess the functional network abnormalities present in male mice that underwent a 7-day subchronic phencyclidine (PCP 10 mg/kg, subcutaneously, once daily) treatment.

The Effects of Peripubertal THC Exposure in Neurodevelopmental Rat Models of Psychopathology.

Adolescent exposure to cannabinoids as a postnatal environmental insult may increase the risk of psychosis in subjects exposed to perinatal insult, as suggested by the two-hit hypothesis of schizophrenia. Here, we hypothesized that peripubertal Δ-tetrahydrocannabinol (aTHC) may affect the impact of prenatal methylazoxymethanol acetate (MAM) or perinatal THC (pTHC) exposure in adult rats. We found that MAM and pTHC-exposed rats, when compared to the control group (CNT), were characterized by adult phenotype relevant to schizophrenia, including social withdrawal and cognitive impairment, as revealed by social interaction test and novel object recognition test, respectively.

Hippo-released WWC1 facilitates AMPA receptor regulatory complexes for hippocampal learning.

Learning and memory rely on changes in postsynaptic glutamergic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type receptor (AMPAR) number, spatial organization, and function. The Hippo pathway component WW and C2 domain-containing protein 1 (WWC1) regulates AMPAR surface expression and impacts on memory performance. However, synaptic binding partners of WWC1 and its hierarchical position in AMPAR complexes are largely unclear.

TRPV1 modulation of contextual fear memory depends on stimulus intensity and endocannabinoid signalling in the dorsal hippocampus.

The transient receptor potential vanilloid type-1 (TRPV1) channels have been implicated in the modulation of aversive responses. The endocannabinoid anandamide acts as an endogenous TRPV1 agonist, exerting opposite functions at TRPV1 and type-1 cannabinoid receptors (CBR). Here we tested the hypothesis that hippocampal TRPV1 modulates contextual fear memory retrieval and investigated the influence of the aversive stimulus intensity as well as the role of endocannabinoid signaling.

Sustained MK-801 induced deficit in a novel probabilistic reversal learning task.

Cognitive flexibility, the ability to adapt to unexpected changes, is critical for healthy environmental and social interactions, and thus to everyday functioning. In neuropsychiatric diseases, cognitive flexibility is often impaired and treatment options are lacking. Probabilistic reversal learning (PRL) is commonly used to measure cognitive flexibility in rodents and humans.

Why do mice squeak? Toward a better understanding of defensive vocalization.

Although mice mostly communicate in the ultrasonic range, they also emit audible calls. We demonstrate that mice selectively bred for high anxiety-related behavior (HAB) have a high disposition for emitting sonic calls when caught by the tail. The vocalization was unrelated to pain but sensitive to anxiolytics.

Chronic Pain and the Endocannabinoid System: Smart Lipids - A Novel Therapeutic Option?

The development of a high-end cannabinoid-based therapy is the result of intense translational research, aiming to convert recent discoveries in the laboratory into better treatments for patients. Novel compounds and new regimes for drug treatment are emerging. Given that previously unreported signaling mechanisms for cannabinoids have been uncovered, clinical studies detailing their high therapeutic potential are mandatory.

Augmented anandamide signalling in the substantia nigra pars reticulata mediates panicolytic-like effects in mice confronted by Crotalus durissus terrificus pit vipers.

Rationale: The endocannabinoid modulation of fear and anxiety due to the on-demand synthesis and degradation is supported by a large body of research. Although it has been proposed that anandamide (AEA) in the substantia nigra pars reticulata (SNpr) seems to be important for the organisation of innate fear-related behaviours, a role for endogenous AEA has yet to be clarified.

Methods: Mice were treated with the fatty acid amide hydrolase (FAAH) selective inhibitor URB597 at different concentrations (0.

Early Blockade of CB1 Receptors Ameliorates Schizophrenia-like Alterations in the Neurodevelopmental MAM Model of Schizophrenia.

In agreement with the neurodevelopmental hypothesis of schizophrenia, prenatal exposure of Sprague-Dawley rats to the antimitotic agent methylazoxymethanol acetate (MAM) at gestational day 17 produces long-lasting behavioral alterations such as social withdrawal and cognitive impairment in adulthood, mimicking a schizophrenia-like phenotype. These abnormalities were preceded at neonatal age both by the delayed appearance of neonatal reflexes, an index of impaired brain maturation, and by higher 2-arachidonoylglycerol (2-AG) brain levels. Schizophrenia-like deficits were reversed by early treatment [from postnatal day (PND) 2 to PND 8] with the CB1 antagonist/inverse agonist AM251 (0.

Myo-Inositol Levels in the Dorsal Hippocampus Serve as Glial Prognostic Marker of Mild Cognitive Impairment in Mice.

Dementia is a devastating age-related disorder. Its therapy would largely benefit from the identification of susceptible subjects at early, prodromal stages of the disease. To search for such prognostic markers of cognitive impairment, we studied spatial navigation in male BALBc vs.

CB1 receptors in corticotropin-releasing factor neurons selectively control the acoustic startle response in male mice.

The endocannabinoid system is an important regulator of the hormonal and behavioral stress responses, which critically involve corticotropin-releasing factor (CRF) and its receptors. While it has been shown that CRF and the cannabinoid type 1 (CB1) receptor are co-localized in several brain regions, the physiological relevance of this co-expression remains unclear. Using double in situ hybridization, we confirmed co-localization in the piriform cortex, the lateral hypothalamic area, the paraventricular nucleus, and the Barrington's nucleus, albeit at low levels.

Inhalational Anesthetics Do Not Deteriorate Amyloid-β-Derived Pathophysiology in Alzheimer's Disease: Investigations on the Molecular, Neuronal, and Behavioral Level.

Background: Studies suggest that general anesthetics like isoflurane and sevoflurane may aggravate Alzheimer's disease (AD) neuropathogenesis, e.g., increased amyloid-β (Aβ) protein aggregation resulting in synaptotoxicity and cognitive dysfunction.

Phytocannabinoids and schizophrenia: Focus on adolescence as a critical window of enhanced vulnerability and opportunity for treatment.

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.

Structural correlates of trauma-induced hyperarousal in mice.

Post-traumatic stress disorder (PTSD) is a chronic disease caused by traumatic incidents. Numerous studies have revealed grey matter volume differences in affected individuals. The nature of the disease renders it difficult to distinguish between a priori versus a posteriori changes.

Orexin 1 and 2 Receptors in the Prelimbic Cortex Modulate Threat Valuation.

The ability to distinguish between threatening (repulsors), neutral and appetitive stimuli (attractors) stimuli is essential for survival. The orexinergic neurons of hypothalamus send projections to the limbic structures, such as different subregions of the medial prefrontal cortex (mPFC), suggesting that the orexinergic mechanism in the prelimbic cortex (PL) is involved in the processing of fear and anxiety. We investigated the role of orexin receptors type 1 (OXR) and type 2 (OXR) in the PL in such processes upon confrontation with an erratically moving robo-beetle in mice.

Exploratory drive, fear, and anxiety are dissociable and independent components in foraging mice.

Anxiety-like behavior of rodents is frequently accompanied by reduced exploration. Here, we identify dissociable components of anxiety, fear, and exploratory drive of sated and foraging mice. With the help of behavioral assays, including the open field task, elevated plus maze, dark-light transition task, and beetle mania task, we demonstrate a general increase in exploration by food restriction.

The stress susceptibility factor FKBP51 controls S-ketamine-evoked release of mBDNF in the prefrontal cortex of mice.

We report here the involvement of the stress-responsive glucocorticoid receptor co-chaperone FKBP51 in the mechanism of secretion of mature BDNF (mBDNF). We used a novel method combining brain microdialysis with a capillary electrophoresis-based immunoassay, to examine mBDNF secretion in the medial prefrontal cortex (mPFC) in freely moving mice. By combining optogenetic, neurochemical (KCl-evoked depolarization), and transgenic (conditional BDNF knockout mice) means, we have shown that the increase in extracellular mBDNF is determined by neuronal activity.

Crosstalk between the transcriptional regulation of dopamine D2 and cannabinoid CB1 receptors in schizophrenia: Analyses in patients and in perinatal Δ9-tetrahydrocannabinol-exposed rats.

Perinatal exposure to Δ-tetrahydrocannabinol (THC) affects brain development and might increase the incidence of psychopathology later in life, which seems to be related to a dysregulation of endocannabinoid and/or dopaminergic systems. We here evaluated the transcriptional regulation of the genes encoding for the cannabinoid CB1 receptor (Cnr1) and the dopamine D2 receptor (Drd2) in perinatal THC-(pTHC) exposed male rats, focusing on the role of DNA methylation analyzed by pyrosequencing. Simultaneously, the molecular and behavioral abnormalities at two different time points (i.

The modulation of striatonigral and nigrotectal pathways by CB1 signalling in the substantia nigra pars reticulata regulates panic elicited in mice by urutu-cruzeiro lancehead pit vipers.

Cannabinoid receptor type 1 (CBR) is widely distributed in the substantia nigra pars reticulata (SNpr). However, the role of CBR at the SNpr level in threatening situations is poorly understood. We investigated the role of CBR in the SNpr on the expression of fear responses in mice confronted with urutu-cruzeiro pit vipers.

cAMP-dependent regulation of HCN4 controls the tonic entrainment process in sinoatrial node pacemaker cells.

It is highly debated how cyclic adenosine monophosphate-dependent regulation (CDR) of the major pacemaker channel HCN4 in the sinoatrial node (SAN) is involved in heart rate regulation by the autonomic nervous system. We addressed this question using a knockin mouse line expressing cyclic adenosine monophosphate-insensitive HCN4 channels. This mouse line displayed a complex cardiac phenotype characterized by sinus dysrhythmia, severe sinus bradycardia, sinus pauses and chronotropic incompetence.

Context and trade-offs characterize real-world threat detection systems: A review and comprehensive framework to improve research practice and resolve the translational crisis.

A better understanding of context in decision-making-that is, the internal and external conditions that modulate decisions-is required to help bridge the gap between natural behaviors that evolved by natural selection and more arbitrary laboratory models of anxiety and fear. Because anxiety and fear are mechanisms evolved to manage threats from predators and other exigencies, the large behavioral, ecological and evolutionary literature on predation risk is useful for re-framing experimental research on human anxiety-related disorders. We review the trade-offs that are commonly made during antipredator decision-making in wild animals along with the context under which the behavior is performed and measured, and highlight their relevance for focused laboratory models of fear and anxiety.

Altered dopamine D3 receptor gene expression in MAM model of schizophrenia is reversed by peripubertal cannabidiol treatment.

Gestational methylazoxymethanol acetate (MAM) treatment produces offspring with adult phenotype relevant to schizophrenia, including positive- and negative-like symptoms, cognitive deficits, dopaminergic dysfunction, structural and functional abnormalities. Here we show that adult rats prenatally treated with MAM at gestational day 17 display significant increase in dopamine D3 receptor (D3) mRNA expression in prefrontal cortex (PFC), hippocampus and nucleus accumbens, accompanied by increased expression of dopamine D2 receptor (D2) mRNA exclusively in the PFC. Furthermore, a significant change in the blood perfusion at the level of the circle of Willis and hippocampus, paralleled by the enlargement of lateral ventricles, was also detected by magnetic resonance imaging (MRI) techniques.