Neonatal leptin deficiency reduces frontal cortex volumes and programs adult hyperactivity in mice

Benjamin C Dexter; Kamal Rahmouni; Taylor Cushman; Gregory M Hermann; Charles Ni; Peg C Nopoulos; Daniel L Thedens; Robert D Roghair

doi:10.1016/j.bbr.2014.01.021

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Neonatal leptin deficiency reduces frontal cortex volumes and programs adult hyperactivity in mice

Journal article

Peer reviewed

Neonatal leptin deficiency reduces frontal cortex volumes and programs adult hyperactivity in mice

Benjamin C Dexter, Kamal Rahmouni, Taylor Cushman, Gregory M Hermann, Charles Ni, Peg C Nopoulos, Daniel L Thedens and Robert D Roghair

Behavioural brain research, Vol.263, pp.115-121

04/15/2014

DOI: 10.1016/j.bbr.2014.01.021

PMCID: PMC3988698

PMID: 24472638

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Abstract

•Perinatal growth restriction increases the risk of adult psychiatric disease.•Growth restriction decreases circulating leptin, a neurotrophic hormone.•Neonatal leptin deficiency decreases frontal lobe volume and programs hyperactivity.•Increased leptin receptor expression suggests a potential therapeutic intervention. 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, 12.5mg/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±0.4mm3, LX 43.8±0.4mm3, 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.

Hyperactivity

Growth restriction

Leptin

Developmental origins

Details

Title: Subtitle: Neonatal leptin deficiency reduces frontal cortex volumes and programs adult hyperactivity in mice
Creators: Benjamin C Dexter - Departments of Pediatrics Carver College of Medicine, University of Iowa, Iowa City, IA 52242, United States
Kamal Rahmouni - Pharmacology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, United States
Taylor Cushman - Departments of Pediatrics Carver College of Medicine, University of Iowa, Iowa City, IA 52242, United States
Gregory M Hermann - Departments of Pediatrics Carver College of Medicine, University of Iowa, Iowa City, IA 52242, United States
Charles Ni - Departments of Pediatrics Carver College of Medicine, University of Iowa, Iowa City, IA 52242, United States
Peg C Nopoulos - Psychiatry Carver College of Medicine, University of Iowa, Iowa City, IA 52242, United States
Daniel L Thedens - Radiology Carver College of Medicine, University of Iowa, Iowa City, IA 52242, United States
Robert D Roghair - Departments of Pediatrics Carver College of Medicine, University of Iowa, Iowa City, IA 52242, United States
Resource Type: Journal article
Publication Details: Behavioural brain research, Vol.263, pp.115-121
DOI: 10.1016/j.bbr.2014.01.021
PMID: 24472638
PMCID: PMC3988698
NLM abbreviation: Behav Brain Res
ISSN: 0166-4328
eISSN: 1872-7549
Publisher: Elsevier B.V
Grant note: DOI: 10.13039/100000002, name: National Institutes of Health, award: HD050359
Language: English
Date published: 04/15/2014
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Neurology; Radiology; Electrical and Computer Engineering; Psychiatry; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Pharmacy Practice and Science; Neuroscience and Pharmacology; Neonatology; Internal Medicine
Record Identifier: 9984040379702771

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