Emotion and Cognition in High and Low Stress Sensitive Mouse Strains: A Combined Neuroendocrine and Behavioral Study in BALB/c and C57BL/6J Mice

Emotionally arousing experiences and stress influence cognitive processes and vice versa. Understanding the relations and interactions between these three systems forms the core of this study. We tested two inbred mouse strains (BALB/c, C57BL/6J; male; 3-month-old) for glucocorticoid stress system markers (expression of MR and GR mRNA and protein in hippocampus, amygdala, and prefrontal cortex; blood plasma corticosterone), used behavioral tasks for emotions and cognitive performance (elevated plus maze, holeboard) to assess the interdependence of these factors. We hypothesize that BALB/c mice have a stress-vulnerable neuroendocrine phenotype and that emotional expressions in BALB/c and C57BL/6J mice will differentially contribute to learning and memory. We applied factor analyses on emotional and cognitive parameters to determine the behavioral structure of BALB/c and C57BL/6J mice. Glucocorticoid stress system markers indeed show that BALB/c mice are more stress-vulnerable than C57BL/6J mice. Moreover, emotional and explorative factors differed between naïve BALB/c and C57BL/6J mice. BALB/c mice display high movement in anxiogenic zones and high risk assessment, while C57BL/6J mice show little movement in anxiogenic zones and display high vertical exploration. Furthermore, BALB/c mice are superior learners, showing learning related behavior which is highly structured and emotionally biased when exposed to a novel or changing situation. In contrast, C57BL/6J mice display a rather “chaotic” behavioral structure during learning in absence of an emotional factor. These results show that stress vulnerability coincides with more emotionality, which drives well orchestrated goal directed behavior to the benefit of cognition. Both phenotypes have their advantage depending on environmental demands

Differential MR/GR Activation in Mice Results in Emotional States Beneficial or Impairing for Cognition

Corticosteroids regulate stress response and influence emotion, learning, and memory via two receptors in the brain, the high-affinity mineralocorticoid (MR) and low-affinity glucocorticoid receptor (GR). We test the hypothesis that MR- and GR-mediated effects interact in emotion and cognition when a novel situation is encountered that is relevant for a learning process. By adrenalectomy and additional constant corticosterone supplement we obtained four groups of male C57BL/6J mice with differential chronic MR and GR activations. Using a hole board task, we found that mice with continuous predominant MR and moderate GR activations were fast learners that displayed low anxiety and arousal together with high directed explorative behavior. Progressive corticosterone concentrations with predominant action via GR induced strong emotional arousal at the expense of cognitive performance. These findings underline the importance of a balanced MR/GR system for emotional and cognitive functioning that is critical for mental health

Overexpression of mineralocorticoid receptors does not affect memory and anxiety-like behavior in female mice

Mineralocorticoid receptors (MRs) have been implicated in behavioral adaptation and learning and memory. Since – at least in humans - MR function seems to be sex-dependent, we examined the behavioral relevance of MR in female mice exhibiting transgenic MR overexpression in the forebrain. Transgenic MR overexpression did not affect contextual fear memory or cued fear learning and memory. Moreover, MR overexpressing and control mice discriminated equally well between fear responses in a combined cue and context fear conditioning paradigm. Also context-memory in an object recognition task was unaffected in MR overexpressing mice. We conclude that MR overexpression in female animals does not affect fear conditioned responses and object recognition memory

Methylphenidate Attenuates Rats' Preference for a Novel Spatial Stimulus Introduced into a Familiar Enviroment: Assessment Using a Force Plate Actometer

Methylphenidate is a psychostimulant widely used in the treatment of attention deficit hyperactivity disorder (ADHD). Here we report a novel paradigm that affords inferences about habituation and attention to a novel stimulus in a familiar environment in a single test session without prior training of the animals. The paradigm was used to assess the effects of methylphenidate (2.5 and 5.0 mg/kg, sc) in young adult, male, Long-Evans rats. Methylphenidate increased locomotor activity during the initial exposure to the test apparatus in a non-dose-related manner. However, upon introduction of a novel spatial stimulus (an alcove) in the familiar environment, methylphenidate-treatment resulted in dose-related increases in distance traveled and inhibition of long dwell times in the alcove, the latter behavior being characteristic of vehicle-treated rats’ response to the alcove condition. These results demonstrate the utility of this paradigm in the elucidation of the behavioral effects of a drug commonly used in the treatment of ADHD. Findings also suggest that species-typical response preferences in rats (e.g., refuge-seeking) may emerge in experimental settings that add spatial novelty to otherwise featureless test enclosures commonly used to assess locomotor activity

Біотехнологічні компанії у процесі консолідації фармацевтичної галузі

Evolution has provided us with a highly flexible neuroendocrine threat system which, depending on threat imminence, switches between active escape and passive freezing. Cortisol, the "stress-hormone", is thought to play an important role in both fear behaviors, but the exact mechanisms are not understood. Using pharmacological functional magnetic resonance imaging we investigated how cortisol modulates the brain's fear systems when humans are under virtual-predator attack. We show dissociated neural effects of cortisol depending on whether escape from threat is possible. During inescapable threat cortisol reduces fear-related midbrain activity, whereas in anticipation of active escape cortisol boosts activity in the frontal salience network (insula and anterior cingulate cortex), which is involved in autonomic control, visceral perception and motivated action. Our findings suggest that cortisol adjusts the human neural threat system from passive fear to active escape, which illuminates the hormone's crucial role in the adaptive flexibility of fear behaviors. Hum Brain Mapp 36:4304-4316, 2015. © 2015 Wiley Periodicals, Inc

Peripheral inflammation acutely impairs human spatial memory via actions on medial temporal lobe glucose metabolism

BACKGROUND Inflammation impairs cognitive performance and is implicated in the progression of neurodegenerative disorders. Rodent studies demonstrated key roles for inflammatory mediators in many processes critical to memory, including long-term potentiation, synaptic plasticity, and neurogenesis. They also demonstrated functional impairment of medial temporal lobe (MTL) structures by systemic inflammation. However, human data to support this position are limited. METHODS Sequential fluorodeoxyglucose positron emission tomography together with experimentally induced inflammation was used to investigate effects of a systemic inflammatory challenge on human MTL function. Fluorodeoxyglucose positron emission tomography scanning was performed in 20 healthy participants before and after typhoid vaccination and saline control injection. After each scanning session, participants performed a virtual reality spatial memory task analogous to the Morris water maze and a mirror-tracing procedural memory control task. RESULTS Fluorodeoxyglucose positron emission tomography data demonstrated an acute reduction in human MTL glucose metabolism after inflammation. The inflammatory challenge also selectively compromised human spatial, but not procedural, memory; this effect that was independent of actions on motivation or psychomotor response. Effects of inflammation on parahippocampal and rhinal glucose metabolism directly mediated actions of inflammation on spatial memory. CONCLUSIONS These data demonstrate acute sensitivity of human MTL to mild peripheral inflammation, giving rise to associated functional impairment in the form of reduced spatial memory performance. Our findings suggest a mechanism for the observed epidemiologic link between inflammation and risk of age-related cognitive decline and progression of neurodegenerative disorders including Alzheimer's disease