Neonatal leptin deficiency reduces frontal cortex volumes and programs adult hyperactivity in mice.
Intrauterine growth restriction and premature delivery decrease circulating levels of the neurotrophic hormone leptin and increase the risk of adult psychiatric disease. In mouse models, neonatal leptin replacement normalizes brain growth and improves the neurodevelopmental outcomes of growth restricted mice, but leptin supplementation of well-grown mice decreases adult locomotor activity. We hypothesized isolated neonatal leptin deficiency is sufficient to reduce adult brain volumes and program behavioral outcomes, including hyperactivity. C57Bl/6 pups were randomized to daily injections of saline or PEG-leptin antagonist (LX, 12.5 mg/kg) from postnatal day 4 to 14. After 4 months, fear conditioning and open field testing were performed followed by carotid radiotelemetry for the measurement of baseline activity and blood pressure. Neonatal LX did not significantly increase cue-based fear or blood pressure, but increased adult locomotor activity during assessment in both the open field (beam breaks: control 930 ± 40, LX 1099 ± 42, P<0.01) and the home cage (radiotelemetry counts: control 4.5 ± 0.3, LX 5.6 ± 0.3, P=0.02). Follow-up MRI revealed significant reductions in adult frontal cortex volumes following neonatal LX administration (control 45. 1 ± 0.4 mm(3), LX 43.8 ± 0.4 mm(3), P=0.04). This was associated with a significant increase in cerebral cortex leptin receptor mRNA expression. In conclusion, isolated neonatal leptin deficiency increases cerebral cortex leptin receptor expression and reduces frontal cortex volumes in association with increased adult locomotor activity. We speculate neonatal leptin deficiency may contribute to the adverse neurodevelopmental outcomes associated with perinatal growth restriction, and postnatal leptin therapy may be protective.
Departments of Pediatrics Carver College of Medicine, University of Iowa, Iowa City, IA 52242, United States.
Benjamin C
BC
Dexter
Pharmacology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, United States; Internal Medicine Carver College of Medicine, University of Iowa, Iowa City, IA 52242, United States.
Kamal
K
Rahmouni
Departments of Pediatrics Carver College of Medicine, University of Iowa, Iowa City, IA 52242, United States.
Taylor
T
Cushman
Departments of Pediatrics Carver College of Medicine, University of Iowa, Iowa City, IA 52242, United States.
Gregory M
GM
Hermann
Departments of Pediatrics Carver College of Medicine, University of Iowa, Iowa City, IA 52242, United States.
Charles
C
Ni
Psychiatry Carver College of Medicine, University of Iowa, Iowa City, IA 52242, United States.
Peg C
PC
Nopoulos
Radiology Carver College of Medicine, University of Iowa, Iowa City, IA 52242, United States.
Daniel L
DL
Thedens
Departments of Pediatrics Carver College of Medicine, University of Iowa, Iowa City, IA 52242, United States. Electronic address: robert-roghair@uiowa.edu.
Robert D
RD
Roghair
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000254:growth & development / Q000473:pathology / Q000503:physiopathology; D003213:Conditioning, Psychological / Q000187:drug effects / Q000502:physiology; D003463:Cues; D004435:Eating / Q000187:drug effects; D005239:Fear / Q000187:drug effects / Q000502:physiology; D005260:Female; D005625:Frontal Lobe / Q000254:growth & development* / Q000473:pathology / Q000503:physiopathology*; D006339:Heart Rate / Q000187:drug effects; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009929:Organ Size; D011595:Psychomotor Agitation / Q000473:pathology / Q000503:physiopathology*; D012333:RNA, Messenger / Q000378:metabolism; D054411:Receptors, Leptin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012737:Sex Factors
D012333:RNA, Messenger; D054411:Receptors, Leptin
Developmental origins; Growth restriction; Hyperactivity; Leptin