Abstract
Maternal deprivation (MD) during neonatal life has diverse long-term behavioral effects and alters the development of the hippocampus and frontal cortex, with several of these effects being sexually dimorphic. MD animals show a marked reduction in their circulating leptin levels, not only during the MD period, but also several days later (PND 13). A neonatal leptin surge occurs in rodents (beginning around PND 5 and peaking between PND 9 and 10) that has an important neurotrophic role. We hypothesized that the deficient neonatal leptin signaling of MD rats could be involved in the altered development of their hippocampus and frontal cortex. Accordingly, a neonatal leptin treatment in MD rats would at least in part counteract their neurobehavioural alterations. MD was carried out in Wistar rats for 24 h on PND 9. Male and female MD and control rats were treated from PND 9 to 13 with rat leptin (3 mg/kg/day sc) or vehicle. In adulthood, the animals were submitted to the open field, novel object memory test and the elevated plus maze test of anxiety. Neuronal and glial population markers, components of the glutamatergic and cannabinoid systems and diverse synaptic plasticity markers were evaluated by PCR and/or western blotting. Main results include: 1) In some of the parameters analyzed, neonatal leptin treatment reversed the effects of MD (eg., mRNA expression of hippocampal IGF1 and protein expression of GFAP and vimentin) partially confirming our hypothesis; 2) The neonatal leptin treatment, per se, exerted a number of behavioral (increased anxiety) and neural effects (eg., expression of the following proteins: NG2, NeuN, PSD95, NCAM, synaptophysin). Most of these effects were sex dependent. An adequate neonatal leptin level (avoiding excess and deficiency) appears to be necessary for its correct neuro-programing effect.
Highlights
Increasing evidence gives support to the fact that early-life stress induces permanent alterations in neurodevelopment [1] that may increase the risk of psychopathology at adulthood [2,3,4]
The ANCOVA performed on the parameters measured in the open field test revealed a significant effect of sex, with females showing the lowest value for the percentage of internal ambulation; and the highest value for total
During the last years we have shown that rats deprived from their mothers during 24 h at postnatal day (PND) 9, maternal deprivation (MD) animals, show a marked reduction in their leptin levels during the period of maternal separation and afterwards, until PND 13 and even in the adulthood [26, 27]
Summary
Increasing evidence gives support to the fact that early-life stress induces permanent alterations in neurodevelopment [1] that may increase the risk of psychopathology at adulthood [2,3,4]. Studies have described deviant behaviors in maternally deprived adolescent animals, i.e. depressive-like responses [13] and increased impulsivity [14], as well as cognitive impairment [15] In addition to these long-term behavioral outcomes, several short and long term brain alterations have been found, affecting neurons and glial cells, growth factors and diverse synaptic plasticity proteins in the hippocampus, cerebral cortex and hypothalamus of MD rats [16]. It is unclear how MD can modify these parameters since there are numerous stressors included in the MD protocol such as lack of maternal care and nutrients during the entire deprivation period, dehydration, and a decrease of body temperature in MD pups [17,18,19]. One of the most striking effects of MD is the marked reduction in circulating leptin levels, during the maternal separation period (PND 9–10), and several days after (PND 13) and in the adulthood [16]
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