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Synergistic Effect of Fish Oil & Choline Supplementation on Brain DHA & Memory (Mouse Study)

Recent research reveals that combining fish oil and choline supplementation may have synergistic effects in boosting levels of brain docosahexaenoic acid (DHA) and memory enhancement in middle-aged mice.

Key Facts:

  • Combining fish oil and choline increased DHA levels in the brain more than either supplement alone in mice.
  • The combination upregulated expression of key fatty acid transport proteins to improve DHA uptake.
  • It also increased acetylcholine synthesis and release in the brain.
  • Middle-aged mice fed the combo performed better on memory tests than controls.

Source: Foods (2023)

The Brain & DHA: An Omega-3 Fatty Acid

The human brain is incredibly enriched with the omega-3 fatty acid docosahexaenoic acid (DHA).

This unique fat is indispensable for proper brain development and maintenance of optimal function throughout life.

Deficiencies in brain DHA levels have been linked to impairments in learning, memory, and various neurological disorders.

However, the body has limited ability to synthesize DHA on its own.

We must obtain this essential nutrient primarily from dietary sources such as fatty fish and fish oil supplements.

Unfortunately, several studies have found that fish oil supplementation alone does not significantly increase brain DHA levels.

This may be because DHA is not efficiently transported across the blood-brain barrier and into the brain tissue.

Most DHA from fish oil exists as triglycerides in the bloodstream.

But specific transport proteins are needed to carry DHA across the blood-brain barrier, either as free fatty acids or as lysophosphatidylcholine (LPC)-DHA.

Recent research investigated whether supplementing the diet of middle-aged mice with a combination of fish oil and choline could optimize DHA delivery to the brain by boosting plasma and brain levels of LPC-DHA.

Choline serves as a precursor for phosphatidylcholine (PC) synthesis, a source of plasma LPC-DHA.

The findings provide compelling evidence that this nutritional strategy has synergistic benefits for memory and brain health.

Fish Oil & Choline Supplementation in Mice (Study): Brain DHA & Cognition

The study, published in Foods, examined the effects of fish oil, choline, or fish oil + choline supplementation in middle-aged male C57BL/6J mice.

After two months of supplementation, mice underwent behavioral testing of learning and memory.

Brains were analyzed to measure DHA levels and expression of fatty acid transport proteins.

What were the findings?

  • Fish oil + choline increased total brain DHA levels more than either supplement alone. It specifically boosted LPC-DHA compared to controls.
  • The combo upregulated the key DHA transport protein MFSD2A in brain microvessels and choroid plexus.
  • It increased expression of fatty acid transporters FATP1 and FABP5 involved in shuttling free DHA into brain cells.
  • On memory tests, the mice supplemented with both performed significantly better than controls.
  • The combo increased acetylcholine synthesis and release, which aids learning.

These results suggest combining fish oil and choline has synergistic effects to enhance DHA delivery to the brain and support memory in middle age.

Optimizing DHA Uptake Across the Blood-Brain Barrier

The blood-brain barrier tightly controls which substances can enter or leave the brain.

Specialized transport proteins are required to carry DHA across this barrier and into brain cells.

The study found fish oil + choline supplementation upregulated three of the main transport proteins:

  1. MFSD2A – Transports LPC-DHA into the brain. Expression increased in brain microvessels.
  2. FATP1 – Shuttles free DHA into brain cells. Expression increased in the cortex.
  3. FABP5 – Binds free DHA for transport into brain cells. Expression increased in the cortex and hippocampus.

By enhancing expression of these transporters, the combo likely optimized delivery of circulating LPC-DHA and free DHA into the brain.

This explains the marked increase of DHA in both the cortex and hippocampus compared to control mice.

The researchers suggest the supplements may indirectly increase transporter expression by activating PPAR receptors.

DHA and choline are both PPAR agonists. Further research is needed to confirm the role of PPAR activation.

Supporting Acetylcholine Synthesis and Signaling

In addition to increasing brain DHA, fish oil + choline supplemented mice showed benefits related to the neurotransmitter acetylcholine:

  • Acetylcholine levels increased by 50% in the cortex and hippocampus.
  • The rate-limiting enzyme choline acetyltransferase increased in cortex.
  • Expression of the synaptic proteins SNAP25 and syntaxin 3 increased.

Acetylcholine is critical for cognition, learning and memory.

Choline provides the raw material to make this neurotransmitter.

The fish oil-choline combo supports both increased acetylcholine synthesis and release for neurotransmission.

Enhancing Memory Performance (Nootropic Effect)

Ultimately, the mice fed both fish oil and choline supplements significantly outperformed control mice on tests assessing spatial learning and memory:

  • They made fewer errors navigating a water maze.
  • They showed longer latency (less errors) in a passive avoidance test.

By getting more DHA into the brain and increasing acetylcholine activity, the combo supplementation appears effective at maintaining memory in middle age.

Future Research Directions

While promising, there are some limitations of this research.

Further studies should investigate:

  • Effects in additional mouse strains, ages, and both sexes.
  • Dose-response effects of different fish oil and choline levels.
  • Effects on humans and optimal human dosing strategies.
  • How other nutrients like UMP and phospholipids may also play a role.
  • Precise mechanisms of transporter regulation and PPAR involvement.

Conclusion: Combining Fish Oil & Choline

In summary, combining fish oil and choline supplementation shows synergistic potential to increase brain DHA levels, support acetylcholine signaling, and improve memory in middle-aged mice.

The combo optimizes DHA uptake into the brain by enhancing expression of key fatty acid transport proteins.

For people looking to increase brain DHA for optimal cognition and memory, the research suggests synergistic benefits from combining fish oil supplements with choline supplements.

Or perhaps combining DHA-rich foods (e.g. cold-water fatty fish) with choline-rich foods (e.g. eggs and meat).

This strategy may help boost brain health and cognitive function in middle age and beyond.

Further research is warranted to determine whether this has a similar effect in humans.


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