title: Modulation of hippocampal theta oscillations and spatial memory by relaxin-3 neurons of the nucleus incertus.
abstract: Hippocampal theta rhythm is thought to underlie learning and memory, and it is well established that "pacemaker" neurons in medial septum (MS) modulate theta activity. Recent studies in the rat demonstrated that brainstem-generated theta rhythm occurs through a multisynaptic pathway via the nucleus incertus (NI), which is the primary source of the neuropeptide relaxin-3 (RLN3). Therefore, this study examined the possible contribution of RLN3 to MS activity, and associated hippocampal theta activity and spatial memory. In anesthetized and conscious rats, we identified the ability of intraseptal RLN3 signaling to modulate neuronal activity in the MS and hippocampus and promote hippocampal theta rhythm. Behavioral studies in a spontaneous alternation task indicated that endogenous RLN3 signaling within MS promoted spatial memory and exploratory activity significantly increased c-Fos immunoreactivity in RLN3-producing NI neurons. Anatomical studies demonstrated axons/terminals from NI/RLN3 neurons make close contact with septal GABAergic (and cholinergic) neurons, including those that project to the hippocampus. In summary, RLN3 neurons of the NI can modulate spatial memory and underlying hippocampal theta activity through axonal projections to pacemaker neurons of the MS. NI/RLN3 neurons are highly responsive to stress and express corticotropin-releasing factor type-1 receptors, suggesting that the effects observed could be an important component of memory processing associated with stress responses.
authors.affiliation: Howard Florey Institute, The University of Melbourne, Victoria 3010, Australia.
authors.forename: Sherie
authors.initials: S
authors.lastname: Ma
authors.forename: Francisco E
authors.initials: FE
authors.lastname: Olucha-Bordonau
authors.forename: M Akhter
authors.initials: MA
authors.lastname: Hossain
authors.forename: Feng
authors.initials: F
authors.lastname: Lin
authors.forename: Chester
authors.initials: C
authors.lastname: Kuei
authors.forename: Changlu
authors.initials: C
authors.lastname: Liu
authors.forename: John D
authors.initials: JD
authors.lastname: Wade
authors.forename: Steven W
authors.initials: SW
authors.lastname: Sutton
authors.forename: Angel
authors.initials: A
authors.lastname: Nuñez
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Gundlach
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal; D001710:Biotin / Q000031:analogs & derivatives / Q000378:metabolism; D003911:Dextrans / Q000378:metabolism; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D006624:Hippocampus / Q000502:physiology*; D007328:Insulin / Q000737:chemistry; D008297:Male; D008568:Memory / Q000187:drug effects / Q000502:physiology*; D046529:Microscopy, Electron, Transmission / Q000379:methods; D050506:Mutant Chimeric Proteins / Q000737:chemistry / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000378:metabolism*; D009434:Neural Pathways / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D009483:Neuropsychological Tests; D010455:Peptides / Q000494:pharmacology; D011149:Pons / Q000166:cytology*; D017729:Presynaptic Terminals / Q000648:ultrastructure; D011506:Proteins / Q000737:chemistry; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012065:Relaxin / Q000737:chemistry / Q000378:metabolism*; D012235:Rhodamines / Q000378:metabolism; D020665:Septum of Brain / Q000187:drug effects / Q000502:physiology; D013028:Space Perception / Q000187:drug effects / Q000502:physiology*; D013057:Spectrum Analysis; D013266:Stilbamidines / Q000378:metabolism; D013826:Theta Rhythm
chemical_list: C049774:2-hydroxy-4,4'-diamidinostilbene, methanesulfonate salt; D003911:Dextrans; D007328:Insulin; C084797:Leydig insulin-like protein; D050506:Mutant Chimeric Proteins; D009419:Nerve Tissue Proteins; D010455:Peptides; D011506:Proteins; D016760:Proto-Oncogene Proteins c-fos; C466742:RLN3 protein, rat; D012235:Rhodamines; D013266:Stilbamidines; C081276:Miniruby; D001710:Biotin; D012065:Relaxin