MCT and beta-hydroxybutirate protect cognitive and synaptic functions

Energy Homeostasis,Energy Substrates,Glucose,Ketone bodies,Neuroprotectors — 7:57 am


Medium-Chain Fatty Acids Improve Cognitive Function and Support In Vitro Synaptic Transmission During Acute Hypoglycemia (1)

The brain can use alternative fuels such as monocarboxylic acids, lactate, and ketones to maintain energy homeostasis (2-8). Fasting or hypoglycemia causes adaptive changes in the brain, including an enhanced ability to utilize alternative fuels. The work conducted by joined teams from Yale School of Medicine, State University of New York, Winthrop University Hospital, Long Island, Department of Psychology, State University of New York, and University at Albany studied how alternative energy substrates influenced cognitive and synaptic functions disturbed by hypoglycemia.

Impaired verbal memory, digit symbol coding, digit span backwards, and map searching was observed during insulin-induced hypoglycemia. Medium-chain triglycerides given in a drink produced higher free fatty acids and beta-hydroxybutyrate levels and returned cognitive performance to normal levels without adversely affecting adrenergic or symptomatic responses to hypoglycemia.

1. Diabetes 58:1237–1244, 2009
2. Hasselbalch SG, Knudsen GM, Jakobsen J, Hageman LP, Holm S, Paulson
OB. Brain metabolism during short-term starvation in humans. J Cereb
Blood Flow Metab 1994;14:125–131
3. Maran A, Cranston I, Lomas J, Macdonald I, Amiel SA. Protection by
lactate of cerebral function during hypoglycaemia. Lancet 1994;343:16–20
4. Veneman T, Mitrakou A, Mokan M, Cryer P, Gerich J. Effect of hyperketonemia
and hyperlacticacidemia on symptoms, cognitive dysfunction,
and counterregulatory hormone responses during hypoglycemia in normal
humans. Diabetes 1994;43:1311–1317
5. Amiel SA, Archibald HR, Chusney G, Williams AJ, Gale EA. Ketone infusion
lowers hormonal responses to hypoglycaemia: evidence for acute cerebral
utilization of a non-glucose fuel. Clin Sci (Lond) 1991;81:189–194
6. Hawkins RA, Williamson DH, Krebs HA. Ketone-body utilization by adult
and suckling rat brain in vivo. Biochem J 1971;122:13–18
7. Pan JW, Rothman TL, Behar KL, Stein DT, Hetherington HP. Human brain
beta-hydroxybutyrate and lactate increase in fasting-induced ketosis.
J Cereb Blood Flow Metab 2000;20:1502–1507
8. Mason GF, Petersen KF, Lebon V, Rothman DL, Shulman GI. Increased
brain monocarboxylic acid transport and utilization in type 1 diabetes.
Diabetes 2006;55:929–934


Q&A: Puzzled by a poster at SFN

Energy Substrates,Ethics in science,Neuroscience FAQ, Q&A — 4:59 am

Original Q&A :: About these Q&A :: Other Q&A

Q: Hi Tanya,

It’s Ingrid again, amused by my beloved topic of excitatory GABA, this time, at SFN 2010. I’m not fortunate enough to be there but nice guys
posted some posters’ photos on our itranet.

My two questions are:

1. Why in table 1, they give SERUM levels of BHB, pyruvate and lactate although the discussion is going on around neuronal behavior?!  Looks
just plane and simple illiterate!

2. Conclusion reads: “Therefore, conventional glucose containing ACSF provides adequate energy supply in vitro.” Do they forgot or
intentionally omitted mentioning immature brain?  A renown expert in developmental metabolism, Dr. Nehlig, one of the coauthors, is it
possible that she agrees with this conclusion, namely that in neonatal slices, neurons happily run on glucose – or this conclusion does not
relate to immature neurons? If so, what this poster is about other than attempting to scandalize Dr. Zilberter team and work?

Thank you Tanya for your time and patience with us inpatient students :)

Ingrid

A: Dear Ingrid,

Remembering your previous question on this topic ,  I guess it’s about Dr Ben-Ari poster, right? I  saw this poster’s photo.

Let’s see how to politely answer your questions. It’s a simple “I have no idea” to your question number 1. You might want to read what surrounds neurons in real brain including energy substrate concentrations in our TIPS review (1), but why SERUM [my capitals] fascinates the authors more than ECF is an enigma to me as it is to you (2).

As to the question number 2, your hypothesis is very interesting although does not help me to answer. Indeed, in all articles by Dr. y Zilberter’s team, works of Dr Nehlig are respectfully and consistently referred to. An example from the Tips review: “Once the onset of suckling takes place, KB become the major fuel for rat brain development” (3) and “In the postnatal developing rat brain, glucose utilization is limited to only about 20% of adult levels” (4).

Notwithstanding, as you quote from the SFN poster, “Therefore, conventional glucose containing ACSF provides adequate energy supply in vitro” –  certainly it cannot be about immature brain. But the title clearly reads: “Depolarizing action of GABA in hippocampal and neocortical IMMATURE [my capitals] neurons depends neither on ketone bodies nor on pyruvate/lactate”. I’m lost here. Sorry I failed!

References

1. Trends Pharmacol Sci. 2010 Sep;31(9):394-401
2. Barriers and fluids that connect and divide blood, brain, and neurons
3. A. Nehlig, Brain uptake and metabolism of ketone bodies in animal models, Prostaglandins Leukot. Essent. Fatty Acids 70 (2004), pp. 265–275
4. A. Nehlig et al., Quantitative autoradiographic measurement of local cerebral glucose utilization in freely moving rats during postnatal development, J. Neurosci. 8 (1988), pp. 2321–2333

Excitatory GABA: “Maybe It’s Not So Exciting After All!”

Energy Substrates,Excitatory GABA — Tags: , , — 4:34 am

The Epilepsy Currents journal, Volume 10, Issue 5, pages 128–130, September/October 2010, published an article titled “Another Look at Early GABAergic Neurotransmission: Maybe It’s Not So Exciting After All!” by Jong M. Rho MD.

Pros and Cons of reconsidering the excitatory GABA dogma according to Dr Rho, in direct quotes *

PROs:

  • “Collectively, these studies cast doubt on the biological relevance of GABA-induced depolarization as evidenced by a multitude of cellular electrophysiological studies.” [1, 2]
  • “Certainly, these authors make a compelling case for a thoughtful re-examination of the time-honored use of ACSF formulations that solely employ glucose as an energy substrate.” **
  • “If the observations of Rheims et al. and Holmgren and colleagues are ultimately validated, then a couple of generations of in vitro studies are likely to be at risk for relegation to the murky domain of artifact.”
CONs

  • “Intriguing as their findings are, the authors have not yet firmly established a mechanism for their general observation ofmetabolic substrate-induced reversal of GABA excitation, despite preliminary evidence invoking the bicarbonate–chloride exchanger.”
  • “Although Rheims et al. and Holmgren and colleagues indicate that their results may be similar to the mechanism of ketogenic action, this link remains speculative at best.”
  • “Whether GABA-evoked depolarization is merely a developmental aberration that is compensated for by differential and age-dependent utilization of energy substrates or whether it is still a fundamental physiological phenomenon important for neuronal maturation, and possibly seizure genesis, remains unclear.” ***

————–

*  all six points are direct quotations of Dr Rho selected to demonstrate his opinion of the papers (1, 2)

** see recent review: Neuronal activity in vitro and the in vivo reality: the role of energy homeostasis

*** There’s a growing body of evidence in favor  the first part of the statement and against its second part showing that the excitatory GABA phenomenon exists only in certain conditions: either brain slices supported by standard ACSF or, if in vivo, during blockade of ketogenesis (3). In healthy immature animals in vivo (3, 4) , as well as in hippocampal preparations in toto (5-7), GABA is shown to always be inhibitory.

References

1. GABA Action in Immature Neocortical Neurons Directly Depends on the Availability of Ketone Bodies. Rheims S, Holmgren CD, Chazal G,Mulder J, Harkany T, Zilberter T, Zilberter Y. J Neurochem 2009;110(4):1330–1338

2. Energy Substrate Availability as a Determinant of Neuronal Resting Potential, GABA Signaling and Spontaneous Network Activity in the Neonatal Cortex In Vitro. Holmgren CD,MukhtarovM,Malkov AE, Popova IY, Bregestovski P, Zilberter Y. J Neurochem 2010;112(4):900–912

3. Rheims S., PhD thesis, Universite de la Mediterranee, 2008

4.  Bremner L, Fitzgerald M & Baccei M. (2006). Functional GABAA-Receptor-Mediated Inhibition in the Neonatal Dorsal Horn. J Neurophysiol 95, 3893-3897

5. Wong, T., et al. (2005) Postnatal development of intrinsic GABAergic rhythms in mouse hippocampus. Neuroscience 134, 107-120

6. Derchansky, M., et al. (2008) Transition to seizures in the isolated immature mouse hippocampus: a switch from dominant phasic inhibition to dominant phasic excitation. J Physiol 586, 477-494

7. Dzhala V et. al., Progressive NKCC1-Dependent Neuronal Chloride Accumulation during Neonatal Seizures The Journal of Neuroscience, (2010) 30(35):11745–11761 • 11745

pH, GDP, energy substrates…

Brain metabolism,Energy Substrates,Methodology — Tags: , , — 6:58 am
1. “The suppression of GDPs was strictly proportional to the fall in pH(i) caused by weak carboxylic acids (l-lactate, d-lactate, or propionate)”
Source:
Spontaneous Network Events Driven by Depolarizing GABA Action in Neonatal Hippocampal Slices are Not Attributable to Deficient Mitochondrial Energy Metabolism. Ruusuvuori E, Kirilkin I, Pandya N, Kaila K. J Neurosci. 2010 Nov 17;30(46)
2.  ”We show that a spontaneous network activity pattern, giant depolarizing potentials (GDPs), characteristic for the neonatal hippocampal slices exposed to artificial cerebrospinal fluid, is strongly inhibited by complementary energy substrates and this effect is unlikely to be caused by a subtle intracellular acidification induced by these compounds”
Source:
Inhibition of spontaneous network activity in neonatal hippocampal slices by energy substrates is not correlated with intracellular acidification. Mukhtarov M, Ivanov A, Zilberter Y, Bregestovski P. J Neurochem. 2011 Jan;116(2):316-21.

Q&A: Neuroscience of movement planning

Neuroscience FAQ, Q&A — 7:32 am

Original Q&A :: About these Q&A :: Other Q&A

QUESTION:

Hi,I’ve heard that scientists have recently done an experiment on brain.they’ve found that when we do an action,first the part of brain related to that action is activated and then the part of brain related to decision about doing that action is activated.I’d like to know the name of this experiment and some information about it.
Thanks a lot!

Banafsheh

ANSWER:

Dear Banafsheh,

I am aware of quite opposite facts. For example, in the work “Patterns of cortical activation during planning of voluntary movement,” Austrian researchers, using the event-related desynchronization (ERD) of upper alpha components made a conclusion: “movement is predetermined more than 1 sec before movement onset” (EEG Clin Neurophysiology, Volume 72, Issue 3, Pages 250-258)
.
If, however, the time intervals we are interesting in smaller intervals, it’s problematic to rely on functional brain imaging when it comes to precise time intervals since this technique, which depends on blood flow velocity, is excessively slow if we are interested in events faster than seconds.

The movement type, for example, grasping, reaching, or eye movements are all planned differently and involve different brain areas with different temporary relationships.

So, if you could be more specific in your question, I would probably be more successful in answering.

Tanya Zilberter

Recommending reading:

princetonbrainandspine.com
uic.edu
en.wikipedia.org

Great Controversies in Neurobiogy

Excitatory GABA,Glucose,Ketone bodies,Methodology,Pyruvate — 9:47 am

“They teach us in our institutes that GABA is excitatory in the neonates, should we still believe it?” (Excitatory GABA scandal?)

There was an interesting development in the Department of Neuroscience of the Brown University who published a provocative recommendation to the Neuro 193E Course under the general title “Great Controversies in Neurobiogy.”

Since 80′s it was becoming a firmly established fact that in immature brain, the reversal potential for GABA receptors was more depolarized, making GABA excitatory and producing a special form of electrical activity named the giant depolarizing potentials, GDP, described by Ben-Ari in hippocampal slices of the immature brain.

“This is something which has been widely described in multiple brain regions by many different labs and is pretty much accepted as fact,” wrote the course’s authors. “However,” continues the chapter, “about a year ago, a couple of papers from the Zilberter’s lab (1, 2) have seriously brought this fact into question.”

The matter is, as multiple prior studies showed [as reviewed in 3, BF], the immature brain “is not very good at metabolizing glucose” due to the immaturity of glycolytic mechanisms and instead it relies on brain fuels alternative to glucose, such as ketones, lactate, and/or pyruvate.

“They noted that almost all papers published using brain slices use artificial cerebro-spinal fluid (ACSF) made with pleny of glucose, but no ketones. Which means that any immature slices cut and maintained in this media will likely be metabolically compromised.”

“They show quite convincingly that adding ketone bodies to ACSF used for immature slices actually makes GABA reversal potential more negative, similar to an adult neuron. Thus they suggest that the depolarizing actin of GABA during early development is an experimental artifact of metabolically-compromised brain slices,” concluded the author.

Source: Dept. of Neuroscience, Brown University. Course Neuro 193E. Last edited by Carlos Aizenman-Stern on Aug 24, 2010 15:34

References

  1. GABA Action in Immature Neocortical Neurons Directly Depends on the Availability of Ketone Bodies. Rheims S, Holmgren CD, Chazal G,Mulder J, Harkany T, Zilberter T, Zilberter Y. J Neurochem 2009;110(4):1330–13382.
  2. Energy Substrate Availability as a Determinant of Neuronal Resting Potential, GABA Signaling and Spontaneous Network Activity in the Neonatal Cortex In Vitro. Holmgren CD,MukhtarovM,Malkov AE, Popova IY, Bregestovski P, Zilberter Y. J Neurochem 2010;112(4):900–912
  3. Neuronal activity in vitro and the in vivo reality: the role of energy homeostasis. Trends Pharmacol Sci. 2010 Sep;31(9):394-401. Epub 2010 Jul 14. Zilberter Y, Zilberter T, Bregestovski P.

Energy substrates and neuroprotection: what does what

Epilepsy,Glucose,Ketone bodies,Lactate,Neuroprotectors,Pyruvate — Tags: — 6:05 am

A few interesting articles about glucose, lactate, and pyruvate
and their neuroprotective functions.

J Neurochem. 2010 Feb 15
Chronic in vitro ketosis is neuroprotective but not anticonvulsant.
Marina Samoilova, Michael Weisspapir, Peter Abdelmalik, Alexander A
Velumian, Peter L Carlen

Chronic in vitro treatment with a ketone body, D-beta-hydroxybutyrate
(DbetaHB), protected the cultures against chronic hypoglycemia,
oxygen-glucose deprivation and NMDA-induced excitotoxicity, but failed
to suppress intrinsic and induced seizure-like activity, indicating
improved neuroprotection is not directly translated into seizure
control. However, chronic in vitro ketosis abolished hippocampal
network hyperexcitability following a metabolic insult, hypoxia,
demonstrating for the first time a direct link between metabolic
resistance and better control of excessive, synchronous, abnormal
electrical activity.

Neuroscience. 2007 Jun 7
Lactate, not pyruvate, is neuronal aerobic glycolysis end product: An
in vitro electrophysiological study. A Schurr, R S Payne

We hypothesized that, in the brain, both aerobic and anaerobic
glycolysis terminate with the formation of lactate from pyruvate by the
enzyme lactate dehydrogenase (LDH). If this hypothesis is correct,
lactate must be the mitochondrial substrate for oxidative energy
metabolism via its oxidation to pyruvate, plausibly by a mitochondrial
LDH

Neurosci Res. 2004 Dec;50 (4):467-74
Glycolysis regulates the induction of lactate utilization for synaptic
potentials after hypoxia in the granule cell of guinea pig hippocampus.
Toshihiro Takata, Bo Yang, Takashi Sakurai, Yasuhiro Okada, Koichi
Yokono

Population spikes are not maintained with lactate following hypoxia in
10 mM glucose medium, but are maintained at their original levels with
lactate after exposure to hypoxia in lower concentration (5 mM) of
glucose.

Neurosci Res. 2003 Jul ;46 (3):333-7
Effects of lactate/pyruvate on synaptic plasticity in the hippocampal
dentate gyrus.
Bo Yang, Takashi Sakurai, Toshihiro Takata, Koichi Yokono

Replacement of glucose with lactate and pyruvate maintained population
spikes after transient depression, and supported a similar degree of
paired-pulse facilitation. These results indicate that monocarboxylates
could serve as sufficient substrates LTP but with less efficiency than
glucose.

Neuroscience. 2007 Jun 7
Lactate, not pyruvate, is neuronal aerobic glycolysis end product: An
in vitro electrophysiological study.A Schurr, R S Payne

 

We hypothesized that, in the brain, both aerobic and anaerobic
glycolysis terminate with the formation of lactate from pyruvate by the
enzyme lactate dehydrogenase (LDH). If this hypothesis is correct,
lactate must be the mitochondrial substrate for oxidative energy
metabolism via its oxidation to pyruvate, plausibly by a mitochondrial
LDH


Neurosci Res. 2004 Dec 50 (4):467-74
Glycolysis regulates the induction of lactate utilization for synaptic
potentials after hypoxia in the granule cell of guinea pig
hippocampus.Toshihiro Takata, Bo Yang, Takashi Sakurai, Yasuhiro Okada,
Koichi Yokono

 

Population spikes are not maintained with lactate following hypoxia in
10 mM glucose medium, but are maintained at their original levels with
lactate after exposure to hypoxia in lower concentration (5 mM) of
glucose.

 

To leave a comment or question click here