Physical activity has been reported to improve cognitive function in humans and rodents, possibly via a brain-derived neurotrophic factor (BDNF)-regulated mechanism. In this study of human subjects, we have assessed the effects of acute and chronic exercise on performance of a face-name matching task, which recruits the hippocampus and associated structures of the medial temporal lobe, and the Stroop word-colour task, which does not, and have assessed circulating concentrations of BDNF and IGF-1 in parallel. The results show that a short period of high-intensity cycling results in enhancements in performance of the face-name matching, but not the Stroop, task. These changes in cognitive function were paralleled by increased concentration of BDNF, but not IGF-1, in the serum of exercising subjects. 3 weeks of cycling training had no effect on cardiovascular fitness, as assessed by VO2 scores, cognitive function, or serum BDNF concentration. Increases in fitness, cognitive function and serum BDNF response to acute exercise were observed following 5 weeks of aerobic training. These data indicate that both acute and chronic exercise improve medial temporal lobe function concomitant with increased concentrations of BDNF in the serum, suggesting a possible functional role for this neurotrophic factor in exercise-induced cognitive enhancement in humans.

This review charts recent advances from a variety of disciplines that create a new perspective on why the multiple hippocampal–anterior thalamic interconnections are together vital for human episodic memory and rodent event memory. Evidence has emerged for the existence of a series of parallel temporal–diencephalic pathways that function in a reciprocal manner, both directly and indirectly, between the hippocampal formation and the anterior thalamic nuclei. These extended pathways also involve the mammillary bodies, the retrosplenial cortex and parts of the prefrontal cortex. Recent neuropsychological findings reveal the disproportionate importance of these hippocampal–anterior thalamic systems for recollective rather than familiarity‐based recognition, while anatomical studies highlight the precise manner in which information streams are kept separate but can also converge at key points within these pathways. These latter findings are developed further by electrophysiological stimulation studies showing how the properties of the direct hippocampal–anterior thalamic projections are often opposed by the indirect hippocampal projections via the mammillary bodies to the thalamus. Just as these hippocampal–anterior thalamic interactions reflect an interdependent system, so it is also the case that pathology in one of the component sites within this system can induce dysfunctional changes to distal sites both directly and indirectly across the system. Such distal effects challenge more traditional views of neuropathology as they reveal how extensive covert pathology might accompany localised overt pathology, and so impair memory.

The anterior thalamic nuclei, a central component of Papez’ circuit, are generally assumed to be key constituents of the neural circuits responsible for certain categories of learning and memory. Supporting evidence for this contention is that damage to either of two brain regions, the medial temporal lobe and the medial diencephalon, is most consistently associated with anterograde amnesia. Within these respective regions, the hippocampal formation and the anterior thalamic nuclei (anteromedial, anteroventral, anterodorsal) are the particular structures of interest. The extensive direct and indirect hippocampal-anterior thalamic interconnections and the presence of theta-modulated cells in both sites further support the hypothesis that these structures constitute a neuronal network crucial for memory and cognition. The major tool in understanding how the brain processes information is the analysis of neuronal output at each hierarchical level along the pathway of signal propagation coupled with neuroanatomical studies. Here, we discuss the electrophysiological properties of cells in the anterior thalamic nuclei with an emphasis on their role in spatial navigation. In addition, we describe neuroanatomical and functional relationships between the anterior thalamic nuclei and hippocampal formation.

The subiculum is a pivotal but under‐investigated structure positioned between the hippocampus proper and entorhinal and other cortices, as well as a range of subcortical structures. The subiculum has a range of electrophysiological and functional properties which are quite distinct from its input areas; given the widespread set of cortical and subcortical areas with which it interacts, it is able to influence activity in quite disparate brain regions. The rules governing plasticity of synaptic transmission in the hippocampal–subicular axis are poorly understood; this axis appears to share some properties in common with the hippocampus proper, but behaves quite differently in other respects. Equally, its functional properties are not well understood; it plays an important but ill‐defined role in spatial navigation, mnemonic processing and control of the response to stress. Here, I review investigations of synaptic plasticity in the hippocampal–subicular pathway, recordings of subicular neurons in the freely moving behaving animal, the effects of behavioural and other stressors on subicular synaptic plasticity, and anatomical data on the dorso‐ventral organization of the subiculum in relation to the hypothalamic–pituitary–adrenal (HPA) axis. I argue that there is a dorso‐ventral segregation of function within the subiculum: the dorsal component appears principally concerned with the processing of information about space, movement and memory, whereas the ventral component appears to play a major regulatory role in the inhibition of the HPA axis.

Schizophrenia is a neurodevelopmental disorder that affects up to 1% of the general population. Various genes show associations with schizophrenia and a very weak nominal association with the tight junction protein, claudin-5, has previously been identified. Claudin-5 is expressed in endothelial cells forming part of the blood-brain barrier (BBB). Furthermore, schizophrenia occurs in 30% of individuals with 22q11 deletion syndrome (22q11DS), a population who are haploinsufficient for the claudin-5 gene. Here, we show that a variant in the claudin-5 gene is weakly associated with schizophrenia in 22q11DS, leading to 75% less claudin-5 being expressed in endothelial cells. We also show that targeted adeno-associated virus-mediated suppression of claudin-5 in the mouse brain results in localized BBB disruption and behavioural changes. Using an inducible ‘knockdown’ mouse model, we further link claudin-5 suppression with psychosis through a distinct behavioural phenotype showing impairments in learning and memory, anxiety-like behaviour and sensorimotor gating. In addition, these animals develop seizures and die after 3–4 weeks of claudin-5 suppression, reinforcing the crucial role of claudin-5 in normal neurological function. Finally, we show that anti-psychotic medications dose-dependently increase claudin-5 expression in vitro and in vivo while aberrant, discontinuous expression of claudin−5 in the brains of schizophrenic patients post mortem was observed compared to age-matched controls. Together, these data suggest that BBB disruption may be a modifying factor in the development of schizophrenia and that drugs directly targeting the BBB may offer new therapeutic opportunities for treating this disorder.