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theses

A ketogenic diet (KD), high in fat and low in carbohydrates, reduces seizure activity in pediatric epilepsy and improves autistic-related behaviors, but the neural mechanisms involved in these improvements are unknown. In the following studies Engrailed-2 (En2) knockout (KO, En2-/-) and wild-type (WT) male mice were fed either a KD or control diet (CD) from postnatal day (PND) 21 to PND 60 (childhood to young adulthood). We hypothesized that a KD fed during this critical time period would alter biogenic amine concentration, metabolism, behavioral deficits, and ultimately neural activation in En2-/- mice. Biogenic amine levels of norepinephrine (NE), dopamine (DA), and serotonin (5-HT) were reduced in forebrain regions and increased in the cerebellum of KO mice, consistent with previous findings. A KD increased hypothalamic NE in WT mice, but not in KO mice. Social behaviors, i.e. frontal contact, were increased and repetitive grooming behaviors reduced in KO-KD. Regardless of previous diet, KO mice displayed increased chow intake post-restraint stress, indicative of a coping response. A KD restored body weight in KO mice by increasing lean mass to WT-KD, but also increased fat mass. KO-KD had enhanced fat metabolism, increased blood glucose response, and reduced blood pressure. KO-KD exposed to a stranger mouse had increased c-Fos immunoreactivity in the cingulate cortex, septal region, and paraventricular nucleus of the hypothalamus (PVN). KO-CD spent more time interacting with a novel object and had increased c-Fos immunoreactivity in the bed nucleus of the stria terminalis (BNST) and PVN. The unique activation of the cingulate and septal region in KO-KD with exposure to a stranger mouse, suggests that these areas could be critical for social behaviors. This research has implications for understanding the impact of a KD on neural development and autistic-like behaviors.

ETD_6679

Ph.D.

Includes bibliographical references

by Jessica Lynn Verpeut

doi:10.7282/T3W95C5Z

ETD doctoral

The author owns the copyright to this work.