Hippocampal NMDA receptors and anxiety: At the interface between cognition and emotion

Abstract

David De Wied had a fundamental interest in the brain and behaviour, with a particular interest in the interface between cognition and emotion, and how impairments at this interface could underlie human psychopathology. The NMDA subtype of glutamate receptor is an important mediator of synaptic plasticity and plays a central role in the neurobiological mechanisms of emotionality, as well as learning and memory. NMDA receptor antagonists affect various aspects of emotionality including fear, anxiety and depression, as well as impairing certain forms of learning and memory. The hippocampus is a key brain structure, implicated in both cognition and emotion. Lesion studies in animals have suggested that dorsal and ventral sub-regions of the hippocampus are differentially involved in dissociable aspects of hippocampus-dependent behaviour. Cytotoxic lesions of the dorsal hippocampus (septal pole) in rodents impair spatial learning but have no effect on anxiety, whereas ventral hippocampal lesions reduce anxiety but are without effect on spatial memory. This role for the ventral hippocampus in anxiety is distinct from the role of the amygdala in other aspects of emotional processing, such as fear conditioning. Recent studies with genetically modified mice have shown that NR1 NMDA receptor subunit deletion, specifically from the granule cells of the dentate gyrus, not only impairs short-term spatial memory but also reduces anxiety. This suggests that NMDA receptors in ventral hippocampus may be a key locus supporting the anxiolytic effects of NMDA receptor antagonists. These data support Gray's neuropsychological account of hippocampal function.

in vivo Variation in Metabotropic Glutamate Receptor Subtype 5 Binding Using Positron Emission Tomography and [11C]ABP688

“…It is possible that the stress of the first PET scan, including arterial and venous catheter placement, caused an increase in the levels of glutamate in the brain (Barkus et al, 2010;Cortese et al, 2010). This increased glutamate may have resulted in lower [ 11 C]ABP688 binding, potentially because of an affinity shift of the receptor for the ligand.…”

Regional inactivations of primate ventral prefrontal cortex reveal two distinct mechanisms underlying negative bias in decision making

“…The amygdala and hippocampus are associated independently with anxiety and anxiolysis (34), and increased gray matter density or activity in both structures is associated with increased sensitivity to negative stimuli (35). Both structures also have wellestablished roles in the enhancement of memory for emotionally The effects of amygdala and anterior hippocampal inactivation or their crossed disconnection on the next day, after antOFC inactivation on a punished day, were compared with the effects of amygdala/hippocampal manipulations on the next day, after punishment in the absence of antOFC inactivation.…”

Hippocampal synaptic plasticity, spatial memory and anxiety

“…Hippocampal lesions also reduce anxiety in a number of different ethological, unconditioned paradigms like the elevated plus maze (EPM) 85,86 that include no explicit role at all for prior learning (and hence competing memories). Furthermore, both pharmacological antagonism and genetic ablation of hippocampal NMDARs are also anxiolytic 51,87 .…”