A Ketogenic Diet Improves Cognition and Has Biochemical Effects in Prefrontal Cortex That Are Dissociable From Hippocampus

Hernandez, Abbi R.; Hernandez, Caesar M.; Campos, Keila; Truckenbrod, Leah; Federico, Quinten; Moon, Brianna; McQuail, Joseph A.; Maurer, Andrew P.; Bizon, Jennifer L.; Burke, Sara N.

doi:10.3389/fnagi.2018.00391

Cited by 111Diet and metabolism studiesDietary Effects on HealthNeuroscience and Neuropharmacology Research

A Ketogenic Diet Improves Cognition and Has Biochemical Effects in Prefrontal Cortex That Are Dissociable From Hippocampus

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Hernandez, Abbi R., Hernandez, Caesar M., Campos, Keila, Truckenbrod, Leah, Federico, Quinten, Moon, Brianna, McQuail, Joseph A., Maurer, Andrew P. +2 more·2018·Frontiers in Aging Neuroscience

DOI 10.3389/fnagi.2018.00391PMC PMC6286979

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Abstract

Age-related cognitive decline has been linked to a diverse set of neurobiological mechanisms, including bidirectional changes in proteins critical for neuron function. Importantly, these alterations are not uniform across the brain. For example, the hippocampus (HPC) and prefrontal cortex (PFC) show distinct patterns of dysfunction in advanced age. Because higher cognitive functions require large-scale interactions across prefrontal cortical and hippocampal networks, selectively targeting an alteration within one region may not broadly restore function to improve cognition. One mechanism for decline that the PFC and HPC share, however, is a reduced ability to utilize glucose for energy metabolism. Although this suggests that therapeutic strategies bypassing the need for neuronal glycolysis may be beneficial for treating cognitive aging, this approach has not been empirically tested. Thus, the current study used a ketogenic diet (KD) as a global metabolic strategy for improving brain function in young and aged rats. After 12 weeks, rats were trained to perform a spatial alternation task through an asymmetrical maze, in which one arm was closed and the other was open. Both young and aged KD-fed rats showed resilience against the anxiogenic open arm, training to alternation criterion performance faster than control animals. Following alternation testing, rats were trained to perform a cognitive dual task that required working memory while simultaneously performing a bi-conditional association task (WM/BAT), which requires PFC-HPC interactions. All KD-fed rats also demonstrated improved performance on WM/BAT. At the completion of behavioral testing, tissue punches were collected from the PFC for biochemical analysis. KD-fed rats had biochemical alterations within PFC that were dissociable from previous results in the HPC. Specifically, MCT1 and MCT4, which transport ketone bodies, were significantly increased in KD-fed rats compared to controls. GLUT1, which transports glucose across the blood brain barrier, was decreased in KD-fed rats. Contrary to previous observations within the HPC, the vesicular glutamate transporter (VGLUT1) did not change with age or diet within the PFC. The vesicular GABA transporter (VGAT), however, was increased within PFC similar to HPC. These data suggest that KDs could be optimal for enhancing large-scale network function that is critical for higher cognition.

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Several clinical studies have shown a positive effect of a ketogenic diet on patients with AD or mild cognitive impairment (MCI), consistent with preclinical results.
“Several clinical studies have shown a positive effect of a ketogenic diet on patients with AD or mild cognitive impairment (MCI), consistent with preclinical results [87–91] (Table 1).”
From Role of diet and its effects on the gut microbiome in the pathophysiology of mental disorders (2022) · cites this paper as [87]

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Hernandez A. R. Hernandez C. M. Campos K. Truckenbrod L. M. Sakarya Y. McQuail J. A. (2017a). The anti-epileptic ketogenic diet alters hippocampal transporter levels and reduces adiposity in aged rats. J. Gerontol. A Biol. Sci. Med. Sci. 73 450– 458. 10.1101/178319 PMC5861916 29040389 · DOI

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A long-term ketogenic diet in young and aged rats has dissociable effects on prelimbic cortex and CA3 ensemble activity
Hernandez, A. R., Barrett, M. E., Lubke, K. N., Maurer, A. P., & Burke, S. (2023) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2023.1274624 · Cited by 5 · see citing works
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Ketogenic Diet-Induced Alterations in Neuronal Signaling-Related Proteins are Not Due to Differences in Synaptosome Protein Levels
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Efectos de la administración de una dieta cetogénica cíclica sobre el proteoma de sinaptosomas corticales de ratones envejecidos
Acuña-Catalán, D. (2024) · Universidad de Chile · doi:10.58011/wkj1-8t82
The study of brain metabolism during aging in rats: the effect of the ketogenic diet and calorie restriction
Roy, M. (2014) · Knowledge UdeS (Institutional Deposit of the University of Sherbrooke)
Ketogenic diet administration later in life improves memory by modifying the synaptic cortical proteome via the PKA signaling pathway in aging mice
Acuña-Catalán, D., Shah, S., Wehrfritz, C., Nomura, M., Acevedo, A., Olmos, C., Quiroz, G., Huerta, H., Bons, J., Ampuero, E., et al. (2024) · Cell Reports Medicine · doi:10.1016/j.xcrm.2024.101593 · Cited by 27 · see citing works

Authors: Hernandez, A. R., Hernandez, C. M., Campos, K., Truckenbrod, L., Federico, Q., Moon, B., McQuail, J. A., Maurer, A. P., Bizon, J. L., & Burke, S. N.
Affiliations: University of Florida (US)
Corresponding author: Burke, Sara N.
ORCID: Hernandez, Abbi R.
Hernandez, Caesar M.
McQuail, Joseph A.
Maurer, Andrew P.
Bizon, Jennifer L.
Burke, Sara N.
Venue: Frontiers in Aging Neuroscience
Publisher: Frontiers Media SA
Published: 2018-12-03
Volume: 10
Pages: 391-391
ISSN: 1663-4365 (ISSN-L)
DOI: 10.3389/fnagi.2018.00391
PMC: PMC6286979
OpenAlex: W2902605370
Cited by: 111
References: 107
Citations by year: 2026: 6 · 2025: 15 · 2024: 11 · 2023: 10 · 2022: 20 · 2021: 19 · 2020: 20 · 2019: 10
FWCI: 8.42
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0/ (unspecified)
Locations: Frontiers in Aging Neuroscience (publishedVersion, cc-by)
Europe PMC (PubMed Central) (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders: Evelyn F. McKnight Brain Research Foundation
National Institute on Aging
Topics: Health Sciences › Medicine › Physiology › Diet and metabolism studies
Health Sciences › Medicine › Physiology › Dietary Effects on Health
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords: ketogenic diet, cognitive aging, prefrontal cortex, hippocampus, MCT1, MCT4, GLUT1, vesicular GABA transporter, vesicular glutamate transporter, working memory, dual-task performance, spatial alternation, brain energy metabolism, glucose utilization, age-related cognitive decline

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A Ketogenic Diet Improves Cognition and Has Biochemical Effects in Prefrontal Cortex That Are Dissociable From Hippocampus

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