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Recovery of hypothalamic NMDA-induced c-fos expression following neonatal glutamate (MSG) lesions
1Department of Obstetrics and Gynaecology, IWK-Grace Health Centre, Halifax, NS, Canada.
Insights
Neonatal exposure to monosodium glutamate (MSG) damages the arcuate nucleus (ARC) but the medial basal hypothalamus (MBH) can recover. Recovery of c-fos expression in the ARC correlates with restored hypothalamic function and normal puberty onset in rats.
Area of Science:
- Neuroscience
- Developmental Biology
- Endocrinology
Background:
- Neonatal brain is vulnerable to neurotoxic insults.
- Monosodium glutamate (MSG) neonatal injection causes arcuate nucleus (ARC) damage and precocious puberty in female rats.
- The medial basal hypothalamus's (MBH) recovery capacity from excitotoxic injury is not fully understood.
Purpose of the Study:
- To investigate the recovery of the MBH from excitotoxic insult using the immediate-early gene c-fos as a marker.
- To assess the ARC's ability to recover following acute and chronic MSG treatment.
- To correlate the recovery of c-fos expression with the restoration of hypothalamic function.
Main Methods:
- Neonatal rats (postnatal day 2) received MSG or saline injections.
- Pups were stimulated with N-methyl-D-aspartate (NMDA) on subsequent days (PD 3-29) to induce c-fos expression.
- Computer-assisted densitometry quantified Fos-like immunoreactivity (FLI) in the ARC.
Main Results:
- Following acute MSG, FLI response was initially absent but recovered to 75% by PD 16 and near full recovery by PD 29.
- Chronic MSG treatment resulted in only 50% FLI recovery by PD 29 and induced unusual hyperactivity/hypoactivity cycles upon NMDA stimulation.
- Recovery of FLI initiated near the third ventricle and radiated outwards; some recovered cells showed abnormal nuclear morphology.
Conclusions:
- The MBH demonstrates significant recovery from neonatal excitotoxic injury, evidenced by the reappearance of c-fos expression.
- The extent of recovery is dependent on the duration of MSG exposure (acute vs. chronic).
- Restoration of normal c-fos expression patterns in the ARC is linked to the recovery of hypothalamic function, including puberty onset.
Abstract:
The neonatal brain is susceptible to neurotoxic insult. In a previous report we showed that a single neonatal injection of MSG, known to cause damage in the arcuate nucleus (ARC), induces a precocious yet otherwise normal puberty in female rats. We have examined this ability of the medial basal hypothalamus (MBH) to recover from an excitotoxic insult using the immediate-early gene c-fos as a developmental marker of ARC response to glutamate receptor stimulation with N-methyl-D-aspartate (NMDA). Groups of neonatal (postnatal day (PD) 2) pups were injected with MSG, then stimulated on subsequent days (PD 3-29) with NMDA, known to induce c-fos expression in ARC. Computer-assisted densitometry was used to quantify Fos-like immunoreactivity (FLI) profiles in ARC. Pups treated neonatally with saline (PD 2) showed a robust, age-specific expression of FLI in the ARC following NMDA treatment. The FLI response was absent in the days immediately following an MSG lesion but subsequently recovered up to 75% of maximum by PD 16. Almost full recovery was seen by PD 29. We also examined the ability of the ARC to recover following chronic MSG treatment (PD 2-8), known to induce extensive hypothalamic damage. These pups displayed an unusual response to subsequent NMDA injection, consisting of 5 min cycles of hyper- and hypoactivity. Stimulation with NMDA revealed only a 50% recovery of FLI even at PD 29. In both treatment groups (acute vs. chronic MSG) the zone of recovery (i.e., reappearance of FLI) was initiated close to the third ventricle and with time radiated towards the periphery of the ARC. Some cells which reacquired FLI in the ARC following lesions presented a highly irregular condensed nuclear morphology. We conclude that the recovery of hypothalamic function (i.e., onset of puberty) after a neonatal MSG lesion is coincident with the reappearance of a normal pattern of c-fos expression in response to NMDA stimulation.
