Context-dependent memory following recurrent hypoglycaemia in non-diabetic rats is mediated via glucocorticoid signalling in the dorsal hippocampus.
Recurrent hypoglycaemia is primarily caused by repeated over-administration of insulin to patients with diabetes. Although cognition is impaired during hypoglycaemia, restoration of euglycaemia after recurrent hypoglycaemia is associated with improved hippocampally mediated memory. Recurrent hypoglycaemia alters glucocorticoid secretion in response to hypoglycaemia; glucocorticoids are well established to regulate hippocampal processes, suggesting a possible mechanism for recurrent hypoglycaemia modulation of subsequent cognition. We tested the hypothesis that glucocorticoids within the dorsal hippocampus might mediate the impact of recurrent hypoglycaemia on hippocampal cognitive processes.



We characterised changes in the dorsal hippocampus at several time points to identify specific mechanisms affected by recurrent hypoglycaemia, using a well-validated 3 day model of recurrent hypoglycaemia either alone or with intrahippocampal delivery of glucocorticoid (mifepristone) and mineralocorticoid (spironolactone) receptor antagonists prior to each hypoglycaemic episode.



Recurrent hypoglycaemia enhanced learning and also increased hippocampal expression of glucocorticoid receptors, serum/glucocorticoid-regulated kinase 1, cyclic AMP response element binding (CREB) phosphorylation, and plasma membrane levels of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartic acid (NMDA) receptors. Both hippocampus-dependent memory enhancement and the molecular changes were reversed by glucocorticoid receptor antagonist treatment.



These results indicate that increased glucocorticoid signalling during recurrent hypoglycaemia produces several changes in the dorsal hippocampus that are conducive to enhanced hippocampus-dependent contextual learning. These changes appear to be adaptive, and in addition to supporting cognition may reduce damage otherwise caused by repeated exposure to severe hypoglycaemia.
Behavioural Neuroscience, University at Albany, 1400 Washington Avenue, Albany, NY, 12222, USA.
Danielle M
DM
Osborne
Biological Sciences, University at Albany, Albany, NY, USA.
Kelsey E
KE
O'Leary
Biological Sciences, University at Albany, Albany, NY, USA.
Dennis P
DP
Fitzgerald
Biological Sciences, University at Albany, Albany, NY, USA.
Alvin J
AJ
George
Biological Sciences, University at Albany, Albany, NY, USA.
Michael M
MM
Vidal
Biological Sciences, University at Albany, Albany, NY, USA.
Brian M
BM
Anderson
Behavioural Neuroscience, University at Albany, 1400 Washington Avenue, Albany, NY, 12222, USA. emcnay@albany.edu.|Biological Sciences, University at Albany, Albany, NY, USA. emcnay@albany.edu.
Ewan C
EC
McNay
D000818:Animals; D003345:Corticosterone / Q000378:metabolism; D005938:Glucocorticoids / Q000627:therapeutic use*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D007003:Hypoglycemia / Q000378:metabolism*; D008297:Male; D015735:Mifepristone / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D013148:Spironolactone / Q000627:therapeutic use
D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D016194:Receptors, N-Methyl-D-Aspartate; D013148:Spironolactone; D015735:Mifepristone; D003345:Corticosterone
AMPA receptor; CREB; Cognition; Glucocorticoids; NMDA receptor; Recurrent hypoglycaemia; Serum/glucocorticoid-regulated kinase 1; Stress; Type 1 diabetes
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