Modulation of hippocampal theta oscillations and spatial memory by relaxin-3 neurons of the nucleus incertus.
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.
Ma
Sherie
S
Howard Florey Institute, The University of Melbourne, Victoria 3010, Australia.
Olucha-Bordonau
Francisco E
FE
Hossain
M Akhter
MA
Lin
Feng
F
Kuei
Chester
C
Liu
Changlu
C
Wade
John D
JD
Sutton
Steven W
SW
Nuñez
Angel
A
Gundlach
Andrew L
AL
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
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