Beta hydroxybutyrate might make you smarter

During physiological ketosis, KB can supply almost 60% of the brain's energy requirement. Plasma KB pass the BBB through monocarboxylic acid transporters (MCT) in a gradient-dependent manner and are readily available for neurons and astrocytes (which are also ketogenic (1)). In fact, the brain is happy without glucose and using ketones (2). Besides being neuroprotective and metabolically more efficient, the main KB, bOHB (3-HB), could enhance memory and learning.

Zou et al (3) tested this hypothesis in mice:

"This study sought to investigate the effect of 3-HB and derivatives on neuroglial cell metabolic activity and gap junctional intercellular communication of hippocampal neurons, to evaluate the hippocampal expression of PUMA-G and proteins related to memory following treatment with 3-HB, and to determine whether 3-hydroxybutyrate methyl ester (3-HBME) improves learning and memory in the normal mouse."

Interneuronal communication can occur indirectly and directly. In the former, chemical synapses are involved, in which transmitters are released into the extracellular space and bind the postsynaptic cell membrane. In the latter, electrical synapses mediate communication. The most prevalent group of electrical synapses, neuronal gap junctions, connect directly the intracellular space of two cells by gap junction channels. Connexin proteins are the structural components of gap junction channels in the nervous system. Specifically, connexin 36 has been involved in learning and memory (4).

3-HB is the endogenous ligand for PUMA-G (5). Its activation in adipose tissue is also produced by nicotinic acid, inhibiting lipolysis and controlling the rate of ketogenesis. This represents an homeostatic mechanism by which 3-HB controls its own production, preventing ketoacidosis. 

Researchers used the Morris water maze for measuring learning and memory, and analyzed hippocampal neuron exposure to 3-HB and derivatives in vitro. All of the metabolites stimulated metabolic activity in neuroglial cells. 3-HMBE increased gap junction intercellular communication, as well as connexin 36 expression by 30% (compared to 12% in mice treated with acetyl-L-carnitine) and pERK2 levels (phosphorylated ERK2, necessary for connexin assembly). Moreover, PUMA-G mRNA was found in the hippocampus, subthalamic nucleus, temporal cortex and frontal cortex, and 3-HBME enhanced the transcription of PUMA-G in the hippocampus.

So this translates to improved memory and learning?

"The escape latency of mice in all groups decreased with time. Overall treatment comparisons indicated that statistically significant differences existed among the groups. Notably, the 30 mM 3-HBME groups took less time (p < 0.05) than the control groups on days 1 and 3–5 to find the platform (Fig. 5B). All treatment groups were faster (p <0.05) than the control group on day 5."

Treatment groups include mice treated with either 3-HBME (20, 30 or 40mg/kg/d) or acetyl-L-carnitine. Control group was water. 

"Paths taken to the platform area on the fifth day of spatial training by mice in the 30 mg/kg/d 3-HBME group were more direct than those taken by mice in the control group, which took more circuitous paths."

Ketotic mice knew exactly what they wanted. 

This causes less total swimming distance (ie. increased efficiency):

"Similar to the escape latency results, the total swimming distance of the 30 mM 3-HBME groups was shorter (p <0.05) than the control groups on days 1 and 3–5. (...) Moreover, the total swimming distance of mice in the 30 mg/kg/d 3-HBME group was shorter (p <0.05) than that of the control or other treatment groups at days 3–5."

A probe test* then was performed to evaluate memory. Three parameteres were measured: the number of crossings of the exact place where the platform had been located, the swimming distance in the quadrant of the former platform position, and the swimming path in the pool. 

Number of times that mice crossed the former position of the hidden platform within 60s:

 

Swimming distance in the platform quadrant:

Swimming path:

Finally, thigmotaxis was lowest in the 30mg/kg/d 3-HMBE group.

A retention test was performed two days after the probe test: 

These test showed that the 30mg/kg/d 3-HMBE group:

a. Crossed more times the exact place where the platform had been located,
b. Had the larger swimming distance in such quadrant,
c. Found the platform faster than the other groups, 
d. Were the most calmed (less thigmotaxis), and
e. Found the platform faster than the other groups during the retention test

These results suggest that 3-HMBE, given at 30mg/kg/d, enhanced learning and memory**.

Researchers used polyhydroxybutyrate (PHB) (a polyhydroxyalkanoate) to produce 3-HB and derivatives. Can we extrapolate these results to physiologically produced 3-HB? The finding that hippocampal neurons expressed PUMA-G receptors is encouraging. As mentioned, 3-HB is the endogenous ligand for PUMA-G, but there seems to be a desensitization of the receptor when exposed to large amounts of 3-HB compared to 3-HBME and 3-HBEE. As PUMA-G interaction with several ligands is not well understood, we cannot draw many conclusions. 

Some studies have evaluated the potential benefit of 3-HB in neurological disorders which compromise memory and learning, such as Alzheimer's disease (AD). For example, in some patients with AD and mild cognitive impairment, MCT oil produces an improvement on cognitive testing and paragraph recall (6), correlated with the increase in plasma ketones. This neuroprotective effect has been explained by the increase in metabolic efficiency associated with 3-HB (7) and inhibition of apoptosis (8), but it might also act through PUMA-G and connexin 36 dependent mechanisms. Further studies should help discovering the molecular pathways involved. In the meantime, maybe schools should start giving students coconut oil shots instead of skim milk.

* The platform was removed from the pool and mice were challenged to a single search trial for 60s. 
** Note that this group performed best than 20mg/kg/d and 40mg/kg/d.


Zou XH, Li HM, Wang S, Leski M, Yao YC, Yang XD, Huang QJ, & Chen GQ (2009). The effect of 3-hydroxybutyrate methyl ester on learning and memory in mice. Biomaterials, 30 (8), 1532-41 PMID: 19111894