Enhanced Recognition Memory through Dual Modulation of Brain Carbonic Anhydrases and Cholinesterases.

This study introduces a novel multitargeting strategy that combines carbonic anhydrase (CA) activators and cholinesterase (ChE) inhibitors to enhance cognitive functions. A series of tacrine-based derivatives with amine/amino acid moieties were synthesized and evaluated for their dual activity on brain CA isoforms and ChEs (AChE and BChE). Several derivatives, notably compounds , , , and , demonstrated potent CA activation, particularly of hCA II and VII, and strong ChE inhibition with subnanomolar to low nanomolar IC values.

Preventing social defeat stress-induced behavioural and neurochemical alterations by repeated treatment with a mix of , and standardized extracts.

Prolonged exposure to stress is a risk factor for the onset of several disorders. Modern life is burdened by a pervasive prevalence of stress, which represents a major societal challenge requiring new therapeutic strategies. In this context, botanical drug-based therapies can have a paramount importance.

Chemogenetic activation or inhibition of histaminergic neurons bidirectionally modulates recognition memory formation and retrieval in male and female mice.

Several lines of evidence demonstrate that the brain histaminergic system is fundamental for cognitive processes and the expression of memories. Here, we investigated the effect of acute silencing or activation of histaminergic neurons in the hypothalamic tuberomamillary nucleus (TMN neurons) in vivo in both sexes in an attempt to provide direct and causal evidence of the necessary role of these neurons in recognition memory formation and retrieval. To this end, we compared the performance of mice in two non-aversive and non-rewarded memory tests, the social and object recognition memory tasks, which are known to recruit different brain circuitries.

Brain-wide neuron quantification toolkit reveals strong sexual dimorphism in the evolution of fear memory.

Fear responses are functionally adaptive behaviors that are strengthened as memories. Indeed, detailed knowledge of the neural circuitry modulating fear memory could be the turning point for the comprehension of this emotion and its pathological states. A comprehensive understanding of the circuits mediating memory encoding, consolidation, and retrieval presents the fundamental technological challenge of analyzing activity in the entire brain with single-neuron resolution.

Gut microbiota and oleoylethanolamide in the regulation of intestinal homeostasis.

A vast literature strongly suggests that the endocannabinoid (eCB) system and related bioactive lipids (the paracannabinoid system) contribute to numerous physiological processes and are involved in pathological conditions such as obesity, type 2 diabetes, and intestinal inflammation. The gut paracannabinoid system exerts a prominent role in gut physiology as it affects motility, permeability, and inflammatory responses. Another important player in the regulation of host metabolism is the intestinal microbiota, as microorganisms are indispensable to protect the intestine against exogenous pathogens and potentially harmful resident microorganisms.

New β-arylchalcogeno amines with procognitive properties targeting Carbonic Anhydrases and Monoamine Oxidases.

Cognitive deficits are enduring and disabling symptoms for many patients with severe mental illness, and these impairments are inadequately addressed by current medications. In this study, we reported the synthesis of β-arylchalcogeno amines bearing sulfurated, selenated, and tellurated moieties (2-4) which are structurally related to amphetamine with good activation properties for Carbonic Anhydrases (CAs) isoforms present in the cortical and hippocampal brain structures (hCA IV and hCA XIV). In addition, these compounds showed selective inhibition against the Monoamine oxidase (MAO) A isoform.

Modulation of Carbonic Anhydrases Activity in the Hippocampus or Prefrontal Cortex Differentially Affects Social Recognition Memory in Rats.

Growing evidence indicates that brain carbonic anhydrases (CAs) are key modulators in cognition, particularly in recognition and aversive memories. Here we described a role for these enzymes also in social recognition memory (SRM), defined as the ability to identify and recognize a conspecific, a process that is of paramount importance in gregarious species, such as rodents and humans. Male adult Wistar rats were submitted to a social discrimination task and, immediately after the sample phase, received bilateral infusions of vehicle, the CAs activator D-phenylalanine (D-Phen, 50 nmols/side), the CAs inhibitor acetazolamide (ACTZ; 10 nmols/side) or the combination of D-Phen and ACTZ directly in the CA1 region of the dorsal hippocampus or in the medial prefrontal cortex (mPFC).

Diet Prevents Social Stress-Induced Maladaptive Neurobehavioural and Gut Microbiota Changes in a Histamine-Dependent Manner.

Exposure to repeated social stress may cause maladaptive emotional reactions that can be reduced by healthy nutritional supplementation. Histaminergic neurotransmission has a central role in orchestrating specific behavioural responses depending on the homeostatic state of a subject, but it remains to be established if it participates in the protective effects against the insults of chronic stress afforded by a healthy diet. By using C57BL/6J male mice that do not synthesize histamine () and their wild type () congeners we evaluated if the histaminergic system participates in the protective action of a diet enriched with polyunsaturated fatty acids and vitamin A on the deleterious effect of chronic stress.

Effects of Alcohol Binge Drinking and Oleoylethanolamide Pretreatment in the Gut Microbiota.

Introduction: Chronic alcohol consumption is known to cause gut dysbiosis (changes in microbiota composition and/or function, disruptive of the normal host-microbiota interactions). However, little is known about the changes that alcohol binge drinking induces in the gut microbiota. Here, we have tested the hypothesis that a protocol of alcohol binge drinking, known to induce neuroinflammation in previous studies, also promotes intestinal dysbiosis, and we explored how oleoylethanolamide (OEA, an acylethanolamide proven to counteract alcohol binge drinking-induced neuroinflammation) pretreatment modulates alcohol-induced dysbiosis.

Oxytocin and Fear Memory Extinction: Possible Implications for the Therapy of Fear Disorders?

Several psychiatric conditions such as phobias, generalized anxiety, and post-traumatic stress disorder (PTSD) are characterized by pathological fear and anxiety. The main therapeutic approach used in the management of these disorders is exposure-based therapy, which is conceptually based upon fear extinction with the formation of a new safe memory association, allowing the reduction in behavioral conditioned fear responses. Nevertheless, this approach is only partially resolutive, since many patients have difficulty following the demanding and long process, and relapses are frequently observed over time.

Different Peas in the Same Pod: The Histaminergic Neuronal Heterogeneity.

The histaminergic neuronal system is recently receiving increasing attention, as much has been learned over the past 25 years about histamine role as a neurotransmitter. Indeed, this amine is crucial in maintaining arousal and provides important contributions to regulate circadian rhythms, energy, endocrine homeostasis, motor behavior, and cognition. The extent to which these distinct physiological functions are operated by independent histamine neuronal subpopulation is unclear.

A Duet Between Histamine and Oleoylethanolamide in the Control of Homeostatic and Cognitive Processes.

In ballet, a pas de deux (in French it means "step of two") is a duet in which the two dancers perform ballet steps together. The suite of dances shares a common theme of partnership. How could we better describe the fine interplay between oleoylethanolamide (OEA) and histamine, two phylogenetically ancient molecules controlling metabolic, homeostatic and cognitive processes? Contrary to the pas de deux though, the two dancers presumably never embrace each other as a dancing pair but execute their "virtuoso solo" constantly exchanging interoceptive messages presumably via vagal afferents, the blood stream, the neuroenteric system.

Short- and Long-Term Social Recognition Memory Are Differentially Modulated by Neuronal Histamine.

The ability of recognizing familiar conspecifics is essential for many forms of social interaction including reproduction, establishment of dominance hierarchies, and pair bond formation in monogamous species. Many hormones and neurotransmitters have been suggested to play key roles in social discrimination. Here we demonstrate that disruption or potentiation of histaminergic neurotransmission differentially affects short (STM) and long-term (LTM) social recognition memory.

Brain histamine and oleoylethanolamide restore behavioral deficits induced by chronic social defeat stress in mice.

The physiological mechanisms underlying the complex interplay between life stressors and metabolic factors is receiving growing interest and is being analyzed as one of the many factors contributing to depressive illness. The brain histaminergic system modulates neuronal activity extensively and we demonstrated that its integrity is necessary for peripheral signals such as the bioactive lipid mediator oleoylethanolamide (OEA) to exert its central actions. Here, we investigated the role of brain histamine and its interaction with OEA in response to chronic social defeat stress (CSDS), a preclinical protocol widely used to study physio-pathological mechanisms underlying symptoms observed in depression.

Activation of carbonic anhydrase isoforms involved in modulation of emotional memory and cognitive disorders with histamine agonists, antagonists and derivatives.

Carbonic anhydrases (CAs, EC 4.2.1.

The role of carbonic anhydrases in extinction of contextual fear memory.

Carbonic anhydrases (CAs; EC 4.2.1.

The anti-inflammatory and immune-modulatory effects of OEA limit DSS-induced colitis in mice.

Fatty acid ethanolamides acting on proliferator-activated receptor (PPAR)-α are among the endogenous lipid molecules that attenuate inflammatory processes and pain sensitivity. Whereas these properties are well-known for palmitoylethanolamide (PEA), the efficacy of oleoylethanolamide (OEA, first described as a satiety hormone synthesized in the jejunum) has been overlooked. In this study, we aimed to evaluate the effect of OEA administration in a mouse model of colitis.

A New Kid on the Block? Carbonic Anhydrases as Possible New Targets in Alzheimer's Disease.

The increase in the incidence of neurodegenerative diseases, in particular Alzheimer's Disease (AD), is a consequence of the world's population aging but unfortunately, existing treatments are only effective at delaying some of the symptoms and for a limited time. Despite huge efforts by both academic researchers and pharmaceutical companies, no disease-modifying drugs have been brought to the market in the last decades. Recently, several studies shed light on Carbonic Anhydrases (CAs, EC 4.

Preventing adolescent stress-induced cognitive and microbiome changes by diet.

Psychological stress during adolescence may cause enduring cognitive deficits and anxiety in both humans and animals, accompanied by rearrangement of numerous brain structures and functions. A healthy diet is essential for proper brain development and maintenance of optimal cognitive functions during adulthood. Furthermore, nutritional components profoundly affect the intestinal community of microbes that may affect gut-brain communication.

Mast Cell-Derived Histamine Regulates Liver Ketogenesis via Oleoylethanolamide Signaling.

The conversion of lipolysis-derived fatty acids into ketone bodies (ketogenesis) is a crucial metabolic adaptation to prolonged periods of food scarcity. The process occurs primarily in liver mitochondria and is initiated by fatty-acid-mediated stimulation of the ligand-operated transcription factor, peroxisome proliferator-activated receptor-α (PPAR-α). Here, we present evidence that mast cells contribute to the control of fasting-induced ketogenesis via a paracrine mechanism that involves secretion of histamine into the hepatic portal circulation, stimulation of liver H receptors, and local biosynthesis of the high-affinity PPAR-α agonist, oleoylethanolamide (OEA).

Oleoylethanolamide treatment affects gut microbiota composition and the expression of intestinal cytokines in Peyer's patches of mice.

The lipid sensor oleoylethanolamide (OEA), an endogenous high-affinity agonist of peroxisome proliferator-activated receptor-α (PPAR-α) secreted in the proximal intestine, is endowed with several distinctive homeostatic properties, such as control of appetite, anti-inflammatory activity, stimulation of lipolysis and fatty acid oxidation. When administered exogenously, OEA has beneficial effects in several cognitive paradigms; therefore, in all respects, OEA can be considered a hormone of the gut-brain axis. Here we report an unexplored modulatory effect of OEA on the intestinal microbiota and on immune response.

Brain histamine modulates recognition memory: possible implications in major cognitive disorders.

Several behavioural tests have been developed to study and measure emotionally charged or emotionally neutral memories and how these may be affected by pharmacological, dietary or environmental manipulations. In this review, we describe the experimental paradigms used in preclinical studies to unravel the brain circuits involved in the recognition and memorization of environmentally salient stimuli devoid of strong emotional value. In particular, we focus on the modulatory role of the brain histaminergic system in the elaboration of recognition memory that is based on the judgement of the prior occurrence of an event, and it is believed to be a critical component of human declarative memory.

Neuronal histamine and the memory of emotionally salient events.

In this review, we describe the experimental paradigms used in preclinical studies to unravel the histaminergic brain circuits that modulate the formation and retrieval of memories associated with aversive events. Emotionally arousing events, especially bad ones, are remembered more accurately, clearly and for longer periods of time than neutral ones. Maladaptive elaborations of these memories may eventually constitute the basis of psychiatric disorders such as generalized anxiety, obsessive-compulsive disorders and post-traumatic stress disorder.