Criteria of validity for animal models of psychiatric disorders: focus on anxiety disorders and depression

Animal models of psychiatric disorders are usually discussed with regard to three criteria first elaborated by Willner; face, predictive and construct validity. Here, we draw the history of these concepts and then try to redraw and refine these criteria, using the framework of the diathesis model of depression that has been proposed by several authors. We thus propose a set of five major criteria (with sub-categories for some of them); homological validity (including species validity and strain validity), pathogenic validity (including ontopathogenic validity and triggering validity), mechanistic validity, face validity (including ethological and biomarker validity) and predictive validity (including induction and remission validity). Homological validity requires that an adequate species and strain be chosen: considering species validity, primates will be considered to have a higher score than drosophila, and considering strains, a high stress reactivity in a strain scores higher than a low stress reactivity in another strain. Pathological validity corresponds to the fact that, in order to shape pathological characteristics, the organism has been manipulated both during the developmental period (for example, maternal separation: ontopathogenic validity) and during adulthood (for example, stress: triggering validity). Mechanistic validity corresponds to the fact that the cognitive (for example, cognitive bias) or biological mechanisms (such as dysfunction of the hormonal stress axis regulation) underlying the disorder are identical in both humans and animals. Face validity corresponds to the observable behavioral (ethological validity) or biological (biomarker validity) outcomes: for example anhedonic behavior (ethological validity) or elevated corticosterone (biomarker validity). Finally, predictive validity corresponds to the identity of the relationship between the triggering factor and the outcome (induction validity) and between the effects of the treatments on the two organisms (remission validity). The relevance of this framework is then discussed regarding various animal models of depression

Assessing learning and memory in pigs

In recent years, there has been a surge of interest in (mini) pigs (Sus scrofa) as species for cognitive research. A major reason for this is their physiological and anatomical similarity with humans. For example, pigs possess a well-developed, large brain. Assessment of the learning and memory functions of pigs is not only relevant to human research but also to animal welfare, given the nature of current farming practices and the demands they make on animal health and behavior. In this article, we review studies of pig cognition, focusing on the underlying processes and mechanisms, with a view to identifying. Our goal is to aid the selection of appropriate cognitive tasks for research into pig cognition. To this end, we formulated several basic criteria for pig cognition tests and then applied these criteria and knowledge about pig-specific sensorimotor abilities and behavior to evaluate the merits, drawbacks, and limitations of the different types of tests used to date. While behavioral studies using (mini) pigs have shown that this species can perform learning and memory tasks, and much has been learned about pig cognition, results have not been replicated or proven replicable because of the lack of validated, translational behavioral paradigms that are specially suited to tap specific aspects of pig cognition. We identified several promising types of tasks for use in studies of pig cognition, such as versatile spatial free-choice type tasks that allow the simultaneous measurement of several behavioral domains. The use of appropriate tasks will facilitate the collection of reliable and valid data on pig cognition

Differences in Mouse Maternal Care Behavior – Is There a Genetic Impact of the Glucocorticoid Receptor?

Depressive episodes are frequently preceded by stressful life events. Evidence from genetic association studies suggests a role for the glucocorticoid receptor (GR), an essential element in the regulation of stress responses, in the pathophysiology of the disorder. Since the stress response system is affected by pregnancy and postpartum-associated changes, it has also been implicated in the pathophysiology of postpartum depression. Using a 2×2 factorial design, we investigated whether a heterozygous deletion of GR would influence maternal care behavior in C57BL/6 and Balb/c mice, two inbred strains known to display qualitative differences in this behavior. Behavioral observation was carried out between postnatal days 1 and 7, followed by a pup retrieval test on postnatal days 7 or 8. While previously noted inter-strain differences were confirmed for different manifestations of caring behavior, self-maintenance and neglecting behaviors as well as the pup retrieval test, no strain-independent effect of the GR mutation was noted. However, an interaction between GR genotype and licking/grooming behavior was observed: it was down-regulated in heterozygous C57BL/6 mice to the level recorded for Balb/c mice. Home cage observation poses minimal disturbance of the dam and her litter as compared to more invasive assessments of dams' emotional behavior. This might be a reason for the absence of any overall effects of the GR mutation, particularly since GR heterozygous animals display a depressive-like phenotype under stressful conditions only. Still, the subtle effect we observed may point towards a role of GR in postpartum affective disorders

Development of an in-vivo active reversible butyrylcholinesterase inhibitor

Alzheimer’s disease (AD) is characterized by severe basal forebrain cholinergic deficit, which results in progressive and chronic deterioration of memory and cognitive functions. Similar to acetylcholinesterase, butyrylcholinesterase (BChE) contributes to the termination of cholinergic neurotransmission. Its enzymatic activity increases with the disease progression, thus classifying BChE as a viable therapeutic target in advanced AD. Potent, selective and reversible human BChE inhibitors were developed. The solved crystal structure of human BChE in complex with the most potent inhibitor reveals its binding mode and provides the molecular basis of its low nanomolar potency. Additionally, this compound is noncytotoxic and has neuroprotective properties. Furthermore, this inhibitor moderately crosses the blood-brain barrier and improves memory, cognitive functions and learning abilities of mice in a model of the cholinergic deficit that characterizes AD, without producing acute cholinergic adverse effects. Our study provides an advanced lead compound for developing drugs for alleviating symptoms caused by cholinergic hypofunction in advanced AD

Genetic Overexpression of NR2B Subunit Enhances Social Recognition Memory for Different Strains and Species

The ability to learn and remember conspecifics is essential for the establishment and maintenance of social groups. Many animals, including humans, primates and rodents, depend on stable social relationships for survival. Social learning and social recognition have become emerging areas of interest for neuroscientists but are still not well understood. It has been established that several hormones play a role in the modulation of social recognition including estrogen, oxytocin and arginine vasopression. Relatively few studies have investigated how social recognition might be improved or enhanced. In this study, we investigate the role of the NMDA receptor in social recognition memory, specifically the consequences of altering the ratio of the NR2B∶NR2A subunits in the forebrain regions in social behavior. We produced transgenic mice in which the NR2B subunit of the NMDA receptor was overexpressed postnatally in the excitatory neurons of the forebrain areas including the cortex, amygdala and hippocampus. We investigated the ability of both our transgenic animals and their wild-type littermate to learn and remember juvenile conspecifics using both 1-hr and 24-hr memory tests. Our experiments show that the wild-type animals and NR2B transgenic mice preformed similarly in the 1-hr test. However, transgenic mice showed better performances in 24-hr tests of recognizing animals of a different strain or animals of a different species. We conclude that NR2B overexpression in the forebrain enhances social recognition memory for different strains and animal species

Selective Cholinergic Depletion in Medial Septum Leads to Impaired Long Term Potentiation and Glutamatergic Synaptic Currents in the Hippocampus

Cholinergic depletion in the medial septum (MS) is associated with impaired hippocampal-dependent learning and memory. Here we investigated whether long term potentiation (LTP) and synaptic currents, mediated by alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionate (AMPA) and N-methyl-D-aspartate (NMDA) receptors in the CA1 hippocampal region, are affected following cholinergic lesions of the MS. Stereotaxic intra-medioseptal infusions of a selective immunotoxin, 192-saporin, against cholinergic neurons or sterile saline were made in adult rats. Four days after infusions, hippocampal slices were made and LTP, whole cell, and single channel (AMPA or NMDA receptor) currents were recorded. Results demonstrated impairment in the induction and expression of LTP in lesioned rats. Lesioned rats also showed decreases in synaptic currents from CA1 pyramidal cells and synaptosomal single channels of AMPA and NMDA receptors. Our results suggest that MS cholinergic afferents modulate LTP and glutamatergic currents in the CA1 region of the hippocampus, providing a potential synaptic mechanism for the learning and memory deficits observed in the rodent model of selective MS cholinergic lesioning

MnemoCity Task: Assessment of Childrens Spatial Memory Using Stereoscopy and Virtual Environments

[EN] This paper presents the MnemoCity task, which is a 3D application that introduces the user into a totally 3D virtual environment to evaluate spatial short-term memory. A study has been carried out to validate the MnemoCity task for the assessment of spatial short-term memory in children, by comparing the children s performance in the developed task with current approaches. A total of 160 children participated in the study. The task incorporates two types of interaction: one based on standard interaction and another one based on natural interaction involving physical movement by the user. There were no statistically significant differences in the results of the task using the two types of interaction. Furthermore, statistically significant differences were not found in relation to gender. The correlations between scores were obtained using the MnemoCity task and a traditional procedure for assessing spatial short-term memory. Those results revealed that the type of interaction used did not affect the performance of children in the MnemoCity task.This work was funded mainly by the Spanish Ministry of Economy and Competitiveness (MINECO) through the CHILDMNEMOS project (TIN2012-37381-C02-01) and confinanced by the European Regional Development Fund (FEDER). Other financial support was received from the Gobierno de Aragon (Departamento de Industria e Innovacion), and Fondo Social Europeo for Aragon.Rodríguez-Andrés, D.; Juan, M.; Mendez Lopez, M.; Pérez Hernández, E.; Lluch Crespo, J. (2016). MnemoCity Task: Assessment of Childrens Spatial Memory Using Stereoscopy and Virtual Environments. PLoS ONE. 11(8):1-28. https://doi.org/10.1371/journal.pone.0161858S12811