Band 22, Heft 3

No abstract available

Animals living in an impoverished environment, i.e., without the possibility of physical and social activity, perform worse on cognitive tests compared to animals in an enriched environment. The same cognitive difference is also observed in humans. However, it is not clear whether this difference is caused by a decrease in cognition due to an impoverished environment or an increase due to an enriched environment. This review discusses the impact of an impoverished environment on cognition in animal experimental studies and human experimental studies with community-dwelling and institutionalized older people. Results show that the cognitive functioning of old rats is more affected by an impoverished environment than young rats. Similarly, sedentary and lonely people (impoverished environment) have worse cognitive functioning and show a faster cognitive decline than physically and socially active people. Institutionalization further aggravates cognitive decline, probably due to the impoverished environment of nursing homes. In institutions, residents spend an unnecessary and excessive amount of time in bed; out of bed they show mainly sedentary or completely passive behavior. In conclusion, older people, especially those that have been institutionalized, have poor levels of physical and social activity, which in turn has a negative impact on cognitive functioning.

The hippocampus is a key brain structure involved in the short- and long-term processing of declarative memory. Since adult hippocampal neurogenesis was first found, numerous studies have tried to establish the contribution of newborn neurons to hippocampus-dependent cognitive functions. However, this large amount of research has generated contradictory results. In this paper, we review the body of evidence investigating the relationship between hippocampal neurogenesis and learning to conclude the functional role of adult-born hippocampal neurons. First, factors that could explain discrepancies among experiments are taken into account. Then, in addition to methodological differences, we emphasize the importance of the age of the newborn neurons studied, as to how their maturation influences both their properties and potential functionality. Next, we discuss which declarative memory components could require involvement of adult hippocampal neurogenesis, taking into consideration the representational demands of the task, its difficulty and the level of performance reached by the subject. Finally, other factors that could modulate neurogenesis and memory, such as stress levels or previous experience of the animal, should also be taken into consideration in interpreting experiments focused on neurogenesis. In conclusion, our analysis of published studies suggests that new adult-born neurons, under certain circumstances, have a crucial and irreplaceable role in hippocampal learning.

A direct relationship has been established between synaptic activity and amyloid-β secretion. Dysregulation of neuronal calcium homeostasis was shown to increase production of amyloid-β, contributing to the initiation of Alzheimer’s disease. Among the different routes of Ca 2+ entry, N -methyl- d -aspartate (NMDA) receptors, a subtype of ionotropic glutamate receptors, are especially involved in this process because of their ability to gate high levels of Ca 2+ influx. These receptors have been extensively studied for their crucial roles in synaptic plasticity that underlies learning and memory but also in neurotoxicity occurring during acute brain injuries and neurodegenerative diseases. For one decade, several studies provided evidence that NMDA receptor activation could have distinct consequences on neuronal fate, depending on their location. Synaptic NMDA receptor activation is neuroprotective, whereas extrasynaptic NMDA receptors trigger neuronal death and/or neurodegenerative processes. Recent data suggest that chronic activation of extrasynaptic NMDA receptors leads to a sustained neuronal amyloid-β release and could be involved in the pathogenesis of Alzheimer’s disease. Thus, as for other neurological diseases, therapeutic targeting of extrasynaptic NMDA receptors could be a promising strategy. Following this concept, memantine, unlike other NMDA receptor antagonists was shown, to preferentially target the extrasynaptic NMDA receptor signaling pathways, while relatively sparing normal synaptic activity. This molecular mechanism could therefore explain why memantine is, to date, the only clinically approved NMDA receptor antagonist for the treatment of dementia.

Depression has traditionally been classified as a disorder of the brain and CNS, with behavioural manifestations which comprise its symptomatology. That symptomatology includes a range of behaviours that also occur during certain immunological responses to pathogens, and this relationship has engendered a large research literature focussed upon the links between cell messenger cytokines and depression. However, despite many studies of those links, the precise contribution that cytokines make to the development of depression remains unclear. In order to explicate the current state of knowledge of this contribution, a review of literature reviews reported during the last five years, plus a sample of empirical studies reported during the last three years, was conducted. Results indicate that there are many plausible pathways between cytokine responses to pathogens and depression, most notably via ‘sickness behaviour’, which supports a model of depression as withdrawal behaviour instigated by the brain and that is based upon primitive responses to uncontrollable and life-threatening environmental challenges. However, the precise nature of the mechanisms by which various cytokines communicate with brain regions and influence functions that are trophic to depressive symptomatology remains to be explicated.

Discovering the basic mechanisms in fear encoding and expression is important in many fields, including psychology, sociology, medicine, and neuroscience. Effective treatment for fear-based pathology depends on understanding how fear is learned and regulated. Among the molecular systems required for fear learning and amygdalar synaptic plasticity, brain derived neurtrophic factor (BDNF) and its high affinity receptor Ntrk2/TrkB have been shown to play essential roles. Therefore, we will focus this review on three main aspects; first of all, the impact of Bdnf polymorphism on fear related characteristics in humans and animal models. Secondly, we will discuss BDNF-TrkB activity regulation by epigenetic, transcriptional and post-translational events, and finally we will discuss TrkB-BDNF signalling in fear learning. BDNF-TrkB and the signalling activated in this particular form of plasticity are becoming crucial players in fear learning and memory thus highlighting these molecules as potential therapeutic targets in fear-related pathologies.

Laboratory rats learn to fear relatively innocuous stimuli which signal the imminent arrival of an innate source of danger, typically brief but aversive foot shock. Much is now known about the neural substrates underling the acquisition, consolidation and subsequent expression of this fear. Rats also learn to fear stimuli which signal learned sources of danger but relatively little is known about the neural substrates underlying this form of fear. Two Pavlovian conditioning paradigms used to study this form of fear are second-order conditioning and sensory preconditioning. In second-order conditioning, rats are first exposed to a signaling relationship between one stimulus, such as a tone, and aversive foot shock, and then to a signaling relationship between a second stimulus, such as a light, and the now dangerous tone. In sensory preconditioning, these phases are reversed: rats are first exposed to a signaling relationship between the light and the tone and then to a signaling relationship between the tone and the foot shock. In both paradigms, rats exhibit fear when tested with the light. In this review paper, we describe the evidence for higher-order forms of conditioning, the conditions which promote this learning and its contents. We compare and contrast the substrates of the learning underlying second-order and sensory preconditioning fear with those known to underlie the better studied first-order conditioned fear. We conclude with some comments as to the role of higher-order processes in anxiety disorders.

Seven mammalian purinergic receptor subunits, denoted P2X1–P2X7, and several spliced forms of these subunits have been cloned. When heterologously expressed, these cDNAs encode ATP-gated non-selective cation channels organized as trimers. All activated receptors produce cell depolarization and promote Ca 2+ influx through their pores and indirectly by activating voltage-gated calcium channels. However, the biophysical and pharmacological properties of these receptors differ considerably, and the majority of these subunits are also capable of forming heterotrimers with other members of the P2X receptor family, which confers further different properties. These channels have three ATP binding domains, presumably located between neighboring subunits, and occupancy of at least two binding sites is needed for their activation. In addition to the orthosteric binding sites for ATP, these receptors have additional allosteric sites that modulate the agonist action at receptors, including sites for trace metals, protons, neurosteroids, reactive oxygen species and phosphoinositides. The allosteric regulation of P2X receptors is frequently receptor-specific and could be a useful tool to identify P2X members in native tissues and their roles in signaling. The focus of this review is on common and receptor-specific allosteric modulation of P2X receptors and the molecular base accounting for allosteric binding sites.

Albumin is the most abundant plasma protein synthesised mainly in the liver. It is also a major component of extracellular fluids including cerebrospinal fluid, interstitial fluid and lymph. Albumin has several biochemical properties including regulation of colloid osmotic pressure of plasma, transportation of hormones, fatty acids, drugs and metabolites across plasma, regulation of microvascular permeability, antioxidant activity, anti-thrombotic activity and anti-inflammatory activity. This multifunctional protein has been implicated in many neurological diseases owing to its ability to regulate hemodynamic properties of the brain circulation as well as the direct neuroprotective actions on neuronal and glial cells. In this review, we summarise various neuroprotective actions of the albumin in the brain. In experimental ischemic stroke, exogenous human serum albumin administration has been found to be neuroprotective via reducing brain swelling, prevention of post-ischemic thrombosis, anti-oxidant activity, hemodilution and increasing the perfusion to the ischemic tissue. Also, human serum albumin administration is currently under clinical trials for treatment of cerebral ischemia. In the experimental models of Alzheimer’s disease, albumin has been implicated in neuroprotection by inhibiting polymerisation and enhancing the clearance of amyloid β. The direct neuroprotective actions on neuronal and glial cells are mediated via endogenously produced albumin or cellular uptake of blood derived albumin. These neuroprotective effects of albumin are partly attributed to anti-oxidant property and modulation of intracellular signalling of neuronal or glial cells. The recent finding of de novo synthesis of albumin in microglial cells directs us to explore newer roles of this endogenously produced multifunctional protein in normal as well as pathological conditions of the brain.

Diverse studies indicate that attention-deficit hyperactivity disorder (ADHD) is associated with alterations in encoding processes, including working or short-term memory. Some ADHD dysfunctional domains are reflected in the spontaneously hypertensive rat (SHR). Because ADHD, drugs and animal models are eliciting a growing interest, hence the aim of this work is to present a brief overview with a focus on the SHR as an animal model for ADHD and memory deficits. Thus, this paper reviews the concept of SHR as a model system for ADHD, comparing SHR, Wistar-Kyoto and Sprague-Dawley rats with a focus on the hypertension level and working, short-term memory and attention in different behavioral tasks, such as open field, five choice serial reaction time, water maze, passive avoidance, and autoshaping. In addition, drug treatments ( d -amphetamine and methylphenidate) are evaluated.