Limits...
Hippocampal NMDA receptors and anxiety: at the interface between cognition and emotion.

Barkus C, McHugh SB, Sprengel R, Seeburg PH, Rawlins JN, Bannerman DM - Eur. J. Pharmacol. (2009)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Experimental Psychology, University of Oxford, South Parks Road, Oxford, OX1 3UD, UK. chris.barkus@psy.ox.ac.uk

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.

Show MeSH

Related in: MedlinePlus

NMDA receptors in the ventral hippocampus mediate anxiety. (a) The successive alleys test of anxiety is a modified version of the elevated plus maze. The apparatus consists of four sections or alleys of increasing anxiogenic character in a linear arrangement. (b) The effects of sham, dorsal hippocampal (dHPC), ventral hippocampal (vHPC) and amygdala lesions on the successive alleys test in rats. vHPC lesioned rats were less anxious than all of the other three groups (e.g. time in Alley 2; F (3,47) = 4.0; P < 0.05, Duncan's pairwise comparisons at P < 0.05), (from McHugh et al., 2004). (c) In situ hybridisation of littermate control animals (left) and DG specific NR1 deleted mice (NR1ΔDG) (right) with NR1 specific probe. The lower panels give a zoom of the hippocampus from the respective upper panels (scale bars: 1 mm). (d) The effect of NR1 NMDA receptor subunit deletion from granule cells of the dentate gyrus on the successive alleys test in mice. NR1ΔDG mice were less anxious than wild-type littermate controls, spending comparatively more time in the more anxiogenic alleys (genotype × alley interaction — F (2,66) = 3.4; P < 0.05, simple main effects; Alley 2 — F (1,88) = 4.1; P < 0.05, Alley 3 — F (1,88) = 4.0; P = 0.05) (from Niewoehner et al., 2007; Supplementary material).
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC2824088&req=5

fig1: NMDA receptors in the ventral hippocampus mediate anxiety. (a) The successive alleys test of anxiety is a modified version of the elevated plus maze. The apparatus consists of four sections or alleys of increasing anxiogenic character in a linear arrangement. (b) The effects of sham, dorsal hippocampal (dHPC), ventral hippocampal (vHPC) and amygdala lesions on the successive alleys test in rats. vHPC lesioned rats were less anxious than all of the other three groups (e.g. time in Alley 2; F (3,47) = 4.0; P < 0.05, Duncan's pairwise comparisons at P < 0.05), (from McHugh et al., 2004). (c) In situ hybridisation of littermate control animals (left) and DG specific NR1 deleted mice (NR1ΔDG) (right) with NR1 specific probe. The lower panels give a zoom of the hippocampus from the respective upper panels (scale bars: 1 mm). (d) The effect of NR1 NMDA receptor subunit deletion from granule cells of the dentate gyrus on the successive alleys test in mice. NR1ΔDG mice were less anxious than wild-type littermate controls, spending comparatively more time in the more anxiogenic alleys (genotype × alley interaction — F (2,66) = 3.4; P < 0.05, simple main effects; Alley 2 — F (1,88) = 4.1; P < 0.05, Alley 3 — F (1,88) = 4.0; P = 0.05) (from Niewoehner et al., 2007; Supplementary material).

Mentions: For example, we assessed anxiety in groups of lesioned rats using the successive alleys test, which is a modified form of the elevated plus maze. The apparatus consists of four sections or alleys of increasing anxiogenic character in a linear arrangement (Fig. 1). The first section is fully enclosed with high walls and is painted black. By gradually reducing the height of the side walls and the width of the arms, and by increasing the brightness, Sections 2, 3 and 4 provide increasingly anxiogenic stimuli. The more anxious an animal, the more time it will spend in the enclosed arms, and the less time it will spend in the more open, exposed (and potentially dangerous) arms. The fact that there are 4 arms of differing anxiogenic character in a linear arrangement is designed to make the test more sensitive by providing a range of anxiogenic conditions. This arrangement also avoids the interpretational difficulties associated with the central square of the elevated plus maze. Animals were placed in the apparatus for 5 min and the times spent in each of the 4 sections were measured. Rats with dorsal or ventral hippocampal lesions, and amygdala lesioned animals were compared to sham-operated controls (McHugh et al., 2004). Whereas sham rats, rats with dorsal hippocampal lesions, and rats with amygdala lesions spent most of their time in the least anxiogenic arm, (Section 1), the animals with ventral hippocampal lesions spent comparatively more time in the more anxiogenic, Section 2 (see Fig. 1). This result was similar to the effects observed when normal rats were given a 2.5 mg/kg dose of chlordiazepoxide. Thus, animals with ventral hippocampal lesions showed reduced anxiety.


Hippocampal NMDA receptors and anxiety: at the interface between cognition and emotion.

Barkus C, McHugh SB, Sprengel R, Seeburg PH, Rawlins JN, Bannerman DM - Eur. J. Pharmacol. (2009)

NMDA receptors in the ventral hippocampus mediate anxiety. (a) The successive alleys test of anxiety is a modified version of the elevated plus maze. The apparatus consists of four sections or alleys of increasing anxiogenic character in a linear arrangement. (b) The effects of sham, dorsal hippocampal (dHPC), ventral hippocampal (vHPC) and amygdala lesions on the successive alleys test in rats. vHPC lesioned rats were less anxious than all of the other three groups (e.g. time in Alley 2; F (3,47) = 4.0; P < 0.05, Duncan's pairwise comparisons at P < 0.05), (from McHugh et al., 2004). (c) In situ hybridisation of littermate control animals (left) and DG specific NR1 deleted mice (NR1ΔDG) (right) with NR1 specific probe. The lower panels give a zoom of the hippocampus from the respective upper panels (scale bars: 1 mm). (d) The effect of NR1 NMDA receptor subunit deletion from granule cells of the dentate gyrus on the successive alleys test in mice. NR1ΔDG mice were less anxious than wild-type littermate controls, spending comparatively more time in the more anxiogenic alleys (genotype × alley interaction — F (2,66) = 3.4; P < 0.05, simple main effects; Alley 2 — F (1,88) = 4.1; P < 0.05, Alley 3 — F (1,88) = 4.0; P = 0.05) (from Niewoehner et al., 2007; Supplementary material).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2824088&req=5

fig1: NMDA receptors in the ventral hippocampus mediate anxiety. (a) The successive alleys test of anxiety is a modified version of the elevated plus maze. The apparatus consists of four sections or alleys of increasing anxiogenic character in a linear arrangement. (b) The effects of sham, dorsal hippocampal (dHPC), ventral hippocampal (vHPC) and amygdala lesions on the successive alleys test in rats. vHPC lesioned rats were less anxious than all of the other three groups (e.g. time in Alley 2; F (3,47) = 4.0; P < 0.05, Duncan's pairwise comparisons at P < 0.05), (from McHugh et al., 2004). (c) In situ hybridisation of littermate control animals (left) and DG specific NR1 deleted mice (NR1ΔDG) (right) with NR1 specific probe. The lower panels give a zoom of the hippocampus from the respective upper panels (scale bars: 1 mm). (d) The effect of NR1 NMDA receptor subunit deletion from granule cells of the dentate gyrus on the successive alleys test in mice. NR1ΔDG mice were less anxious than wild-type littermate controls, spending comparatively more time in the more anxiogenic alleys (genotype × alley interaction — F (2,66) = 3.4; P < 0.05, simple main effects; Alley 2 — F (1,88) = 4.1; P < 0.05, Alley 3 — F (1,88) = 4.0; P = 0.05) (from Niewoehner et al., 2007; Supplementary material).
Mentions: For example, we assessed anxiety in groups of lesioned rats using the successive alleys test, which is a modified form of the elevated plus maze. The apparatus consists of four sections or alleys of increasing anxiogenic character in a linear arrangement (Fig. 1). The first section is fully enclosed with high walls and is painted black. By gradually reducing the height of the side walls and the width of the arms, and by increasing the brightness, Sections 2, 3 and 4 provide increasingly anxiogenic stimuli. The more anxious an animal, the more time it will spend in the enclosed arms, and the less time it will spend in the more open, exposed (and potentially dangerous) arms. The fact that there are 4 arms of differing anxiogenic character in a linear arrangement is designed to make the test more sensitive by providing a range of anxiogenic conditions. This arrangement also avoids the interpretational difficulties associated with the central square of the elevated plus maze. Animals were placed in the apparatus for 5 min and the times spent in each of the 4 sections were measured. Rats with dorsal or ventral hippocampal lesions, and amygdala lesioned animals were compared to sham-operated controls (McHugh et al., 2004). Whereas sham rats, rats with dorsal hippocampal lesions, and rats with amygdala lesions spent most of their time in the least anxiogenic arm, (Section 1), the animals with ventral hippocampal lesions spent comparatively more time in the more anxiogenic, Section 2 (see Fig. 1). This result was similar to the effects observed when normal rats were given a 2.5 mg/kg dose of chlordiazepoxide. Thus, animals with ventral hippocampal lesions showed reduced anxiety.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Experimental Psychology, University of Oxford, South Parks Road, Oxford, OX1 3UD, UK. chris.barkus@psy.ox.ac.uk

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.

Show MeSH
Related in: MedlinePlus