title: High-fat diet impairs spatial memory and hippocampal intrinsic excitability and sex-dependently alters circulating insulin and hippocampal insulin sensitivity.
abstract: BACKGROUND
  High-fat diets promoting obesity/type-2 diabetes can impair physiology and cognitive performance, although sex-dependent comparisons of these impairments are rarely made. Transient reductions in Ca(2+)-dependent afterhyperpolarizations (AHPs) occur during memory consolidation, enhancing intrinsic excitability of hippocampal CA1 pyramidal neurons. In rats fed standard diets, insulin can enhance memory and reduce amplitude and duration of AHPs.
  
  
  METHODS
  Effects of chronic high-fat diet (HFD) on memory, circulating insulin, and neuronal physiology were compared between young adult male and female Long-Evans rats. Rats fed for 12 weeks (from weaning) a HFD or a control diet (CD) were then tested in vivo prior to in vitro recordings from CA1 pyramidal neurons.
  
  
  RESULTS
  The HFD significantly impaired spatial memory in both males and females. Significant sex differences occurred in circulating insulin and in the insulin sensitivity of hippocampal neurons. Circulating insulin significantly increased in HFD males but decreased in HFD females. While the HFD significantly reduced hippocampal intrinsic excitability in both sexes, CA1 neurons from HFD females remained insulin-sensitive but those from HFD males became insulin-insensitive.
  
  
  CONCLUSIONS
  Findings consistent with these have been characterized previously in HFD or senescent males, but the effects observed here in young females are unique. Loss of CA1 neuronal excitability, and sex-dependent loss of insulin sensitivity, can have significant cognitive consequences, over both the short term and the life span. These findings highlight needs for more research into sex-dependent differences, relating systemic and neural plasticity mechanisms in metabolic disorders.
authors.affiliation: Cognition & Neuroscience Program, School of Behavioral & Brain Sciences, University of Texas at Dallas, 800 W. Campbell Rd., Richardson, TX 75080 USA.
authors.forename: Erica L
authors.initials: EL
authors.lastname: Underwood
authors.affiliation: Cognition & Neuroscience Program, School of Behavioral & Brain Sciences, University of Texas at Dallas, 800 W. Campbell Rd., Richardson, TX 75080 USA.
authors.forename: Lucien T
authors.identifier: 0000-0001-8878-0221
authors.initials: LT
authors.lastname: Thompson
keywords: AHP; CA1; Diabetes; Glucose regulation; High-fat diet; Hippocampal excitability; Sex differences; Spatial memory
references.citation: J Neurophysiol. 2002 Aug;88(2):621-6
references.pmid: 12163515
references.citation: Proc Natl Acad Sci U S A. 2008 Sep 30;105(39):15154-9
references.pmid: 18799739
references.citation: J Neurophysiol. 1996 Sep;76(3):1836-49
references.pmid: 8890296
references.citation: J Neurosci. 1996 Sep 1;16(17):5536-46
references.pmid: 8757265
references.citation: Expert Rev Neurother. 2011 May;11(5):677-708
references.pmid: 21539488
references.citation: Diabet Med. 2001 Oct;18(10):803-10
references.pmid: 11678970
references.citation: Nat Neurosci. 2005 Nov;8(11):1542-51
references.pmid: 16234810
references.citation: J Alzheimers Dis. 2012;30(2):413-22
references.pmid: 22430529
references.citation: Neuropsychopharmacology. 2006 Jun;31(6):1097-111
references.pmid: 16554740
references.citation: J Neurosci. 2005 Mar 9;25(10):2609-16
references.pmid: 15758171
references.citation: J Neurosci. 2003 Jul 16;23(15):6338-44
references.pmid: 12867518
references.citation: Intern Med J. 2012 May;42(5):484-91
references.pmid: 22372522
references.citation: Int J Environ Res Public Health. 2012 May;9(5):1663-76
references.pmid: 22754464
references.citation: Neurobiol Learn Mem. 2003 Nov;80(3):223-33
references.pmid: 14521865
references.citation: J Neurosci. 2013 Oct 9;33(41):16158-69
references.pmid: 24107948
references.citation: J Neurosci. 1999 Mar 1;19(5):1814-23
references.pmid: 10024365
references.citation: Endocrinology. 2008 May;149(5):2628-36
references.pmid: 18276751
references.citation: Neurobiol Learn Mem. 2010 May;93(4):546-53
references.pmid: 20176121
references.citation: Diabetes Obes Metab. 2007 Nov;9(6):840-52
references.pmid: 17924866
references.citation: Diabet Med. 2012 Mar;29(3):328-36
references.pmid: 22023662
references.citation: J Neurosci. 2000 Jul 15;20(14):5476-82
references.pmid: 10884331
references.citation: Lancet Diabetes Endocrinol. 2014 Jan;2(1):56-64
references.pmid: 24622669
references.citation: Trends Neurosci. 2006 Oct;29(10):587-99
references.pmid: 16942805
references.citation: Behav Brain Res. 2007 Aug 22;182(1):57-66
references.pmid: 17590450
references.citation: Neurology. 2011 May 3;76(18):1568-74
references.pmid: 21536637
references.citation: Neurobiol Aging. 2010 Feb;31(2):224-43
references.pmid: 18479783
references.citation: J Mol Endocrinol. 2006 Jun;36(3):485-501
references.pmid: 16720718
references.citation: Science. 1984 Nov 30;226(4678):1089-92
references.pmid: 6494926
references.citation: Neurosci Lett. 1995 Jun 2;192(1):5-8
references.pmid: 7675309
references.citation: Brain Res. 1975 Mar 7;85(3):423-36
references.pmid: 1111846
references.citation: Child Neuropsychol. 2004 Mar;10(1):36-52
references.pmid: 14977514
references.citation: Brain Cogn. 2007 Jun;64(1):86-91
references.pmid: 17349729
references.citation: Nat Rev Neurosci. 2006 Jun;7(6):477-84
references.pmid: 16688123
references.citation: Neurobiol Aging. 2011 Nov;32(11):1949-63
references.pmid: 20053478
references.citation: J Gerontol A Biol Sci Med Sci. 2016 Jan;71(1):30-9
references.pmid: 25659889
references.citation: Neural Plast. 2016;2016:7385314
references.pmid: 26819773
references.citation: CNS Drugs. 2013 Jul;27(7):505-14
references.pmid: 23719722
references.citation: Brain Res. 2012 Jan 30;1435:99-104
references.pmid: 22206925
references.citation: J Physiol. 1989 Feb;409:171-90
references.pmid: 2585290
references.citation: J Neurophysiol. 1992 Dec;68(6):2100-9
references.pmid: 1491260
references.citation: Cell Metab. 2012 Dec 5;16(6):723-37
references.pmid: 23217255
references.citation: Eur J Neurosci. 1998 Apr;10(4):1518-23
references.pmid: 9749805
references.citation: Nat Neurosci. 2008 Mar;11(3):309-17
references.pmid: 18278039
references.citation: Neurobiol Aging. 2005 Dec;26 Suppl 1:42-5
references.pmid: 16257476
references.citation: J Clin Invest. 2012 Apr;122(4):1316-38
references.pmid: 22476197
references.citation: FASEB J. 2001 Oct;15(12):2121-30
references.pmid: 11641238
references.citation: J Neurosci. 2012 Feb 15;32(7):2241-7
references.pmid: 22396398
references.citation: Diabetes Care. 2014 Jan;37 Suppl 1:S81-90
references.pmid: 24357215
references.citation: J Am Geriatr Soc. 2003 Feb;51(2):169-77
references.pmid: 12558712
references.citation: Biol Mood Anxiety Disord. 2012 Feb 07;2:3
references.pmid: 22738383
references.citation: J Neurophysiol. 2003 Oct;90(4):2171-9
references.pmid: 12815013
references.citation: J Neurophysiol. 2004 Oct;92(4):2346-56
references.pmid: 15190096
references.citation: J Physiol. 2007 Feb 1;578(Pt 3):799-818
references.pmid: 17138601
references.citation: Hippocampus. 2012 Aug;22(8):1703-19
references.pmid: 22367983
references.citation: Alzheimer Dis Assoc Disord. 2015 Jul-Sep;29(3):206-12
references.pmid: 25650694
references.citation: Biophys J. 2013 Jan 22;104(2):281-3
references.pmid: 23442848
references.citation: Neurobiol Learn Mem. 2015 Mar;119:34-41
references.pmid: 25613546
references.citation: Learn Mem. 2014 Sep 16;21(10):556-63
references.pmid: 25227250
references.citation: Neuroscience. 2003;118(2):577-83
references.pmid: 12699792
references.citation: J Neurosci. 2009 Apr 15;29(15):4750-5
references.pmid: 19369544
references.citation: Pain. 2005 Sep;117(1-2):1-5
references.pmid: 16098670
references.citation: Pflugers Arch. 2004 May;448(2):187-96
references.pmid: 14727118
references.citation: Braz J Biol. 2002 Nov;62(4A):609-14
references.pmid: 12659010
references.citation: J Clin Endocrinol Metab. 2008 Apr;93(4):1339-44
references.pmid: 18230654
references.citation: Brain Res. 1991 Mar 8;543(1):148-52
references.pmid: 2054668
references.citation: J Neurosci. 2004 Jun 9;24(23):5301-6
references.pmid: 15190101
references.citation: Physiol Rev. 2001 Apr;81(2):741-66
references.pmid: 11274343
references.citation: Ann N Y Acad Sci. 2001 Mar;933:265-77
references.pmid: 12000027
references.citation: J Nutr. 2003 Apr;133(4):1081-7
references.pmid: 12672923
references.citation: J Neurophysiol. 2009 Nov;102(5):2763-70
references.pmid: 19726729
references.citation: Science. 2007 Mar 9;315(5817):1426-9
references.pmid: 17347444
references.citation: Neuroscience. 1999;93(2):557-63
references.pmid: 10465439
references.citation: Arch Neurol. 2012 Sep;69(9):1170-5
references.pmid: 22710333
references.citation: J Neuroinflammation. 2015 Apr 02;12:63
references.pmid: 25889938
references.citation: J Biol Chem. 1999 Dec 3;274(49):34893-902
references.pmid: 10574963
references.citation: J Neurophysiol. 2000 May;83(5):2554-61
references.pmid: 10805657
references.citation: Biophys J. 2012 Dec 19;103(12):2446-54
references.pmid: 23260046
references.citation: Nature. 2010 Jun 10;465(7299):690
references.pmid: 20535186
references.citation: Obesity (Silver Spring). 2010 Mar;18(3):463-9
references.pmid: 19730425
references.citation: J Neurosci. 2002 Mar 1;22(5):1618-28
references.pmid: 11880492
references.citation: Mol Cell Biol. 1999 Oct;19(10):7203-15
references.pmid: 10490655
references.citation: Nature. 1992 Oct 15;359(6396):638-41
references.pmid: 1406995
references.citation: J Neurosci. 2011 Feb 16;31(7):2638-48
references.pmid: 21325532
references.citation: J Physiol. 2004 Jan 15;554(Pt 2):255-61
references.pmid: 14500775
references.citation: Neurobiol Aging. 2013 Aug;34(8):1977-87
references.pmid: 23545425
references.citation: Genes Brain Behav. 2007 Mar;6(2):192-200
references.pmid: 16827921
references.citation: Psychoneuroendocrinology. 1996 Jan;21(1):51-65
references.pmid: 8778904
references.citation: Proc Natl Acad Sci U S A. 1986 Apr;83(8):2733-7
references.pmid: 3458232
references.citation: J Neurophysiol. 1986 Jun;55(6):1268-82
references.pmid: 2426421
references.citation: Eur J Pharmacol. 2004 Apr 19;490(1-3):5-12
references.pmid: 15094069
references.citation: Diabetes. 2003 Mar;52(3):682-7
references.pmid: 12606509
references.citation: Ageing Res Rev. 2002 Apr;1(2):181-207
references.pmid: 12039438
references.citation: J Neurosci Methods. 2015 Apr 15;244:123-35
references.pmid: 25280984