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A Brain Wrought Without Omega-3

2 February 2011. A diet deficient in omega-3 fatty acids interferes with synaptic function, according to a study published January 30 in Nature Neuroscience. Mice chronically deprived of this essential fatty acid showed abnormalities in neurotransmission and plasticity mediated by endocannabinoid receptors, and they seemed prone to anxiety and depression-like behaviors.

Although not directly related to schizophrenia, the study adds to the evidence suggesting a link between improper ratios of different omega fatty acids and mental health (Parker et al., 2006). Present within synaptic membranes, these polyunsaturated fatty acids constitute building blocks of the nervous system, and their incorporation during brain development and beyond may be compromised in brain disorders like schizophrenia (Berger et al, 2006). Consistent with this line of thinking, a study last year suggested that omega-3 fatty acid supplementation with fish oil could help prevent or delay psychosis in vulnerable teens (see SRF related news story).

Humans need to get omega-3 fatty acids from their diet, mainly from fish and certain nuts and vegetables, but the typical Western diet is notorious for its lack of these and a concomitant rise in omega-6 fatty acids. This imbalance prompted Sophie Layé of University of Bordeaux and Olivier Manzoni of INSERM in France to model omega-3 fatty acid deficiency in mice to better understand the impacts in the brain. To mimic a lifelong omega-3 deficiency, the researchers fed a diet lacking omega-3 fatty acid precursors but rich in the omega-6 ones to pregnant mice and to the resulting offspring. They found that this imbalanced diet did indeed translate into abnormal fatty acid levels in the brains of the offspring: in the whole brain and in the prefrontal cortex (PFC), a region implicated in emotional behavior and depression, researchers measured a substantial decrease in the amount of omega-3 fatty acids but an increase in omega-6 fatty acids when compared to mice receiving a diet with appropriate amounts of omega-3 and omega-6 precursors.

Enter endocannabinoids
First authors Mathieu Lafourcade, Thomas Larrieu, and Susana Mato then looked for synaptic abnormalities in brain slices made from mice receiving the omega-3-deficient diet. They focused on the cannabinoid system because polyunsaturated fatty acids can form endogenous ligands ("endocannabinoids") for cannabinoid receptors located on the axon terminals of glutamate-releasing neurons. There, activation of the receptor (CB1R) decreases the amount of neurotransmitter released.

The researchers looked for a form of endocannabinoid-dependent plasticity that they had previously characterized (Lafourcade et al., 2007). While tetanic (repeated) stimulation of the excitatory inputs onto PFC neurons resulted in long-term depression of synaptic currents in control slices, the same protocol did not diminish the size of currents from omega-3-deficient slices. Similarly, this endocannabinoid-mediated plasticity was not found in the nucleus accumbens, a node in brain circuits potentially involved in mood disorders (see SRF related news story), as well as schizophrenia (see, e.g., Floresco et al., 2009), in the omega-3-deficient mice. Other types of synaptic plasticity remained intact, suggesting that the effect of the diet was specific to endocannabinoid-mediated processes.

Further experiments suggested that this defect in plasticity might result from desensitized CB1Rs not working to their full potential. When researchers exposed control slices to a CB1R agonist, this provoked a robust inhibition of excitatory synaptic potentials—an effect consistent with pre-synaptic CB1R activation turning down neurotransmitter release. However, the same treatment produced a much smaller inhibition in slices from omega-3-deficient mice, indicating that the CB1Rs were not as sensitive. Other experiments argued that this diminished function stemmed from CB1Rs that were functionally uncoupled from their effector G proteins, rather than reduced CB1R expression in the omega-3-deficient group. The CB1Rs may have been desensitized in the first place by increased levels of circulating endocannabinoids, something the researchers found indirect evidence for in the omega-3-deficient mice.

A diet for depression?
The researchers then explored the behavioral consequences of the omega-3-deficient diet in mice. In a forced swim test, the amount of time spent immobile—considered a despair-like behavior—was greater in omega-3-deficient mice than in controls. In both groups, this immobility was reversed by the antidepressant imipramine. In the social realm, the omega-3-deficient mice did not explore a new mouse as much as controls did, though they moved around just as much. In an open-field test, which tracks the explorations of a mouse placed inside a walled arena, the omega-3-deficient group spent less time in the center of the arena and more time along the "safer" walls than did controls—behaviors linked to anxiety. To see whether these behaviors were linked to CB1R function, the researchers injected mice with a CB1R agonist to activate CB1Rs. This tilted the control mice toward anxious behavior—spending significantly more time along the walls and less time in the center of the arena; in contrast, the agonist had no effect on the omega-3-deficient group, consistent with the idea that CB1R function was impaired in these mice.

The study begins to outline in mechanistic detail the effects of an omega fatty acid unbalanced diet, and highlights a potential role for the cannabinoid system in mental health. More research will have to explore the links between omega-3-fatty acids, CB1Rs, the PFC, and emotion regulation, and decide whether any of these players offer therapeutic insights into treating depression or schizophrenia.—Michele Solis.

Reference:
Lafourcade M, Larrieu T, Mato S, Duffaud A, Sepers M, Matias I, De Smedt-Peyrusse V, Labrousse VF, Bretillon L, Matute C, Rodríguez-Puertas R, Layé S, Manzoni OJ. Nutritional omega-3 deficiency abolishes endocannabinoid-mediated neuronal functions. Nat Neurosci. 2011 Jan 30. Abstract

Comments on News and Primary Papers


Primary Papers: Nutritional omega-3 deficiency abolishes endocannabinoid-mediated neuronal functions.

Comment by:  Leonora LongCynthia Shannon Weickert (SRF Advisor)
Submitted 28 July 2011
Posted 28 July 2011

Omega-3 Fatty Acid Levels and Mental Health: Focus on Endocannabinoids and Schizophrenia
Deficiency in dietary omega-3 fatty acid intake appears to favor higher levels of omega-6 acids, which has implications for metabolites downstream of these two fatty acid precursors, including endogenous cannabinoids. While the excellent recent study in Nature Neuroscience (Lafourcade et al., 2011) did not find that increased omega-6 levels corresponded to altered levels of the two major endocannabinoids, 2-AG and anandamide, it did show that it led to a functional reduction of cannabinoid CB1R efficacy and decoupling of CB1R from its inhibitory G protein signaling. This is extremely interesting, given the evidence for changes in endocannabinoid function in schizophrenia (De Marchi et al., 2003; Eggan et al., 2008; Eggan et al., 2010; Dalton et al., 2011). While it is still not understood whether such changes are causal to the pathophysiology of schizophrenia, it is increasingly clear that modification of the endocannabinoid system could have implications for normal development (Bossong and Niesink, 2010; Malone et al., 2010), especially given the association of cannabis use with increased risk for schizophrenia (Moore et al., 2007).

Therefore, further investigation into this area would be welcome, since there are several unanswered questions on this subject. For example, Lafourcade et al. investigated the effect of modifying maternal dietary fatty acid intake on rodent behaviors relevant to symptoms of depression and anxiety, but it is not known whether such dietary modification, either pre- or postnatal, also detrimentally affects other rodent behaviors related to schizophrenia such as cognitive flexibility, response to pharmacological challenge with dopaminergic or glutamatergic agents, sensorimotor gating, and complex social behavior. In the context of human studies, is there a link between fatty acid and endocannabinoid levels in humans with differing dietary intake of omega-3 fatty acids, and if so, does such a link explain the occurrence of psychotic symptoms? Does omega-3 fatty acid treatment in animal models of schizophrenia or in human trials alter endocannabinoid ligands, receptors, and metabolic enzymes in the periphery and/or brain, and if so, how are these alterations related to improvement of or reversal of schizophrenia symptoms? Finally, while a reduced omega-3:omega-6 ratio appears detrimental to endocannabinoid function, would there be a limit to potential benefits of omega-3 supplementation; i.e., would it be harmful if the omega-3:omega-6 ratio was increased beyond a certain point, since overall increase in this ratio as a result of omega-3 supplementation may adversely impact on endocannabinoid levels in the opposite direction (Batetta et al., 2009; Wood et al., 2010)? The extent to which this has been tested, particularly during development, is not clear. In sum, the possible link between dietary fatty acids and brain cannabinoid system is an interesting area for schizophrenia researchers to consider, and is ripe for further investigation.

References:

Batetta B, Griinari M, Carta G, Murru E, Ligresti A, Cordeddu L, Giordano E, Sanna F, Bisogno T, Uda S, Collu M, Bruheim I, Di Marzo V, Banni S. Endocannabinoids may mediate the ability of (n-3) fatty acids to reduce ectopic fat and inflammatory mediators in obese Zucker rats. J Nutr . 2009 Aug 1 ; 139(8):1495-501. Abstract

Bossong MG, Niesink RJ. Adolescent brain maturation, the endogenous cannabinoid system and the neurobiology of cannabis-induced schizophrenia. Prog Neurobiol . 2010 Nov 1 ; 92(3):370-85. Abstract

Dalton VS, Long LE, Weickert CS, Zavitsanou K. Paranoid Schizophrenia is Characterized by Increased CB(1) Receptor Binding in the Dorsolateral Prefrontal Cortex. Neuropsychopharmacology . 2011 Jul 1 ; 36(8):1620-30. Abstract

De Marchi N, De Petrocellis L, Orlando P, Daniele F, Fezza F, Di Marzo V. Endocannabinoid signalling in the blood of patients with schizophrenia. Lipids Health Dis . 2003 Aug 19 ; 2():5. Abstract

Eggan SM, Hashimoto T, Lewis DA. Reduced cortical cannabinoid 1 receptor messenger RNA and protein expression in schizophrenia. Arch Gen Psychiatry . 2008 Jul 1 ; 65(7):772-84. Abstract

Eggan SM, Stoyak SR, Verrico CD, Lewis DA. Cannabinoid CB1 receptor immunoreactivity in the prefrontal cortex: Comparison of schizophrenia and major depressive disorder. Neuropsychopharmacology . 2010 Sep 1 ; 35(10):2060-71. Abstract

Lafourcade M, Larrieu T, Mato S, Duffaud A, Sepers M, Matias I, De Smedt-Peyrusse V, Labrousse VF, Bretillon L, Matute C, Rodríguez-Puertas R, Layé S, Manzoni OJ. Nutritional omega-3 deficiency abolishes endocannabinoid-mediated neuronal functions. Nat Neurosci . 2011 Mar ; 14(3):345-50. Abstract

Malone DT, Hill MN, Rubino T. Adolescent cannabis use and psychosis: epidemiology and neurodevelopmental models. Br J Pharmacol . 2010 Jun 1 ; 160(3):511-22. Abstract

Moore TH, Zammit S, Lingford-Hughes A, Barnes TR, Jones PB, Burke M, Lewis G. Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review. Lancet . 2007 Jul 28 ; 370(9584):319-28. Abstract

Wood JT, JS Williams, et al. Dietary docosahexaenoic acid supplementation alters select physiological endocannabinoid-system metabolites in brain and plasma. J Lipid Res. 2010;51(6):1416-1423. Abstract

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Comments on Related News


Related News: BDNF In the Nucleus Accumbens—Too Much of a Good Thing?

Comment by:  NN Kudryavtseva
Submitted 23 February 2006
Posted 23 February 2006

Berton and colleagues show very impressive data of molecular studies demonstrating numerous changes of gene expression in brain under repeated social defeats. However, the behavioral or pharmacological data that the authors use to support the development of depression in socially defeated mice may be interpreted otherwise.

The authors used decreases in the level of social communication (they called it avoidance-approach behavior) in defeated losers as parameters of depression. We repeatedly noted in our experiments on the social model of depression induced by social confrontations in mice of the C57BL/6J strain (Kudryavtseva et al., 1991) that even one or two social defeats lead to a decrease of communication in mice. Thus, avoidance behavior cannot be used as a specific parameter of depression; rather, it may represent anxiety. However, our experiments demonstrated that longer experience of defeats over 20-30 days (but not 10 days, as used by Berton et al.) in male mice produces development of a depression-like state (anxious depression): similarities of symptoms, etiological factors (social unavoidable emotional stress, permanent anxiety), sensitivity to chronic antidepressants and anxiolytics (imipramine, tianeptine, citalopram, fluoxetine, buspirone, etc.), as well as brain neurochemistry changes (serotonergic and dopaminergic systems) (Kudryavtseva et al., 1991; for reviews see Kudryavtseva, Avgustinovich, 1998; Avgustinovich et al., 2004).

In our molecular studies, we also demonstrated changes of gene expression in the brains of male mice after daily agonistic interactions. Three experimental groups were compared: the losers with repeated experience of social defeats; winners with repeated aggression accompanied by social victories; and controls (very important—the same strain). In has been shown that MAOA and SERT mRNA levels in the raphe nuclei of the losers were higher than in the controls and winners. TH and DAT gene expression in the ventral tegmental area was higher and κ opioid receptor gene expression was lower in the winners in comparison with the losers and controls (see Filipenko et al., 2001; 2002; Goloshchapov et al., 2005; reviewed in Kudryavtseva et al., 2004). Thus, there are different specific changes in gene expression in different brain areas in male mice with opposite social behaviors—winners and losers.

As for BDNF, there is an emerging body of data suggesting that different mood disorders are associated with changed BDNF. I think that changes of BDNF gene expression in the losers may be nonspecific for depression state. Expression of the BDNF gene in the winners should be investigated to confirm or reject this idea.

Again, Berton et al. (2006) have demonstrated very impressive data. Taking into consideration these data and our molecular studies, it may be suggested that the sensory contact paradigm (sensory contact model) may be used for the study of association between agonistic behavior and gene expression. We called this scientific direction “From behavior to gene” (reviewed in Kudryavtseva et al., 2004), as an addition to the traditional “From gene to behavior.”

References:

Kudryavtseva NN, Bakshtanovskaya IV, Koryakina LA. Social model of depression in mice of C57BL/6J strain. Pharmacol Biochem Behav. 1991 Feb;38(2):315-20. Abstract

Kudryavtseva NN, Avgustinovich DF. (1998) Behavioral and physiological markers of experimental depression induced by social conflicts (DISC). Aggress Behav. 24:271-286.

Filipenko ML, Alekseyenko OV, Beilina AG, Kamynina TP, Kudryavtseva NN. Increase of tyrosine hydroxylase and dopamine transporter mRNA levels in ventral tegmental area of male mice under influence of repeated aggression experience. Brain Res Mol Brain Res. 2001 Nov 30;96(1-2):77-81. Abstract

Filipenko ML, Beilina AG, Alekseyenko OV, Dolgov VV, Kudryavtseva NN. Repeated experience of social defeats increases serotonin transporter and monoamine oxidase A mRNA levels in raphe nuclei of male mice. Neurosci Lett. 2002 Mar 15;321(1-2):25-8. Abstract

Kudryavtseva et al. (2004) Changes in the expression of monoaminergic genes under the influence of repeated experience of agonistic interactions: From behavior to gene. Genetika, 40(6):732-748.

Avgustinovich DF, Alekseenko OV, Bakshtanovskaia IV, Koriakina LA, Lipina TV, Tenditnik MV, Bondar' NP, Kovalenko IL, Kudriavtseva NN. [Dynamic changes of brain serotonergic and dopaminergic activities during development of anxious depression: experimental study] Usp Fiziol Nauk. 2004 Oct-Dec;35(4):19-40. Review. Russian. Abstract

Goloshchapov AV, Filipenko ML, Bondar NP, Kudryavtseva NN, Van Ree JM. Decrease of kappa-opioid receptor mRNA level in ventral tegmental area of male mice after repeated experience of aggression. Brain Res Mol Brain Res. 2005 Apr 27;135(1-2):290-2. Epub 2005 Jan 6. Abstract

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Related News: Thinking Outside the Pillbox: Fish Oil and Exercise for Schizophrenia?

Comment by:  William Carpenter, SRF Advisor (Disclosure)
Submitted 16 February 2010
Posted 16 February 2010

The most controversial recommendation being considered by the DSM-V Psychoses Work Group involves creating a risk syndrome section and placing psychosis risk as a class in this new section. The September 2009 issue of Schizophrenia Bulletin carried a concept piece on the risk syndrome by Heckers, a validity report by Woods et al., and an editorial detailing Work Group considerations by me. Reliability has been established among experts, but to eventually make this recommendation for DSM-V, we will have to demonstrate reliability in ordinary clinical settings by ordinary clinicians. Even then, substantial opposition is anticipated, and it seems more likely headed for the appendix (in need of further study) than prime time as a diagnostic class.

Opposition is based primarily on three concerns: 1) high false-positive rates, 2) harm related to stigma and excessive drug prescribing, and 3) lack of an evidence-based therapeutic approach with documented efficacy and effectiveness. The first two can be rebutted to some extent by giving emphasis to the potential advantages for the true positive cases. Regarding the false positive cases, it can be emphasized that distress, disability, and help-seeking are obligatory for the proposed criteria. Therefore, these persons would still be exposed to clinical care that might include excessive medication and stigma. Furthermore, they would still have the risk of an uninformative diagnosis.

On the third point, it is worth noting that the DSM is not a therapeutic manual. Nonetheless, as a practical matter, I have assumed that opposition would melt away if a safe and effective treatment for true positive cases were known, and if the treatment did more good than harm for false positive cases. Amminger et al. move the field a giant step forward in this regard. Omega-3 free fatty acids are thought to be associated with general health benefits without significant adverse effects. I take them daily and hope to live forever. Their report of substantially reduced conversion-to- psychotic-illness rates is reinforced by secondary analyses showing benefits for psychopathology. The number needed to treat is four, a very small number, and I assume the number needed to harm is very high (this could not be determined in the present study since adverse events did not exceed placebo, but infinity is not excluded).

This important report urgently calls for replication or refutation. If confirmed, it provides a basis for hope that therapeutics with a novel compound may substantially improve the fate of persons at risk for psychotic illness. If confirmed, I expect the opposition to formally identifying persons as at risk for psychosis will melt away. We may be closer to issues related to identifying and treating hypercholesterolemia than we are to the supposed harm associated with elevating the risk syndrome to the level of classification in DSM-V.

References:

Heckers S. Who is at risk for a psychotic disorder? Schizophr Bull. 2009 Sep;35(5):847-50. Epub 2009 Jul 24. Abstract

Woods SW, Addington J, Cadenhead KS, Cannon TD, Cornblatt BA, Heinssen R, Perkins DO, Seidman LJ, Tsuang MT, Walker EF, McGlashan TH. Validity of the prodromal risk syndrome for first psychosis: findings from the North American Prodrome Longitudinal Study. Schizophr Bull. 2009 Sep;35(5):894-908. Abstract

Carpenter WT. Anticipating DSM-V: should psychosis risk become a diagnostic class? Schizophr Bull. 2009 Sep;35(5):841-3. Abstract

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Related News: Thinking Outside the Pillbox: Fish Oil and Exercise for Schizophrenia?

Comment by:  Stuart Maudsley
Submitted 19 February 2010
Posted 19 February 2010

The recent work of Pajonk and colleagues is one of the most recent demonstrations of the beneficial neurological actions of physical exercise. Physical activity not only can improve cardiovascular health directly, but also appears to engender a strong neurotrophic effect that can be isolated somewhat from the cardiovascular actions. Recreational physical activity has been demonstrated to improve learning and memory functions in healthy adults (Winter et al., 2007), reduce the risk of dementia in elderly patients (Karp et al., 2006; Vaynman and Gomez-Pinilla, 2006), attenuate progression and development of Alzheimer’s disease (AD) (Wilson et al., 2002), and productively increase brain volume in areas concerned with spatial memory and executive function (Colcombe et al., 2006; Erickson et al., 2009). This final aspect of physical exercise, i.e., actual increased central nervous system development, is the subject of the Pajonk et al. study. Rather than the neurological developmental effects of exercise upon healthy, aged, or AD patients, Pajonk and colleagues have studied the actions of exercise upon the hippocampal regions of schizophrenic patients.

Hippocampal function and structure are sensitive to the environment
The hippocampus, primarily concerned with the acquisition and transfer of short-term memories, has been demonstrated to be exceptionally sensitive to volume alteration with cognitive or physical exercise paradigms (Boyke et al., 2008; Erickson et al., 2009; Pereira et al., 2007). Although pathology of the hippocampus is primarily linked to AD (Maudsley et al., 2007), abnormalities in the structure of this brain region have been reported in schizophrenia (Reif et al., 2006) and may contribute to defects in neural plasticity in this area.

Pajonk et al. have attempted to apply the well-known effects of exercise upon hippocampal structure and volume to patients presenting with schizophrenia. This group recruited patients with schizophrenia along with a healthy control group. Half of the schizophrenic group was exposed to a coordinated and supervised physical exercise regimen (cycling), while the rest of the schizophrenic patients were occupied for a similar period of time with a hand-eye coordination skill that did not induce significant physical exertion (table football). The control individuals were also placed on an exercise regimen (cycling), but oddly, none was subjected to the table football task, a potential flaw in the study’s experimental design.

Physical exercise increases hippocampal volume in schizophrenic patients
Crucial neurophysiological measurements were made in all the experimental subjects at the beginning of the study and after three months of the protocols. One of the primary indices measured, using magnetic resonance imaging, was the change in relative hippocampal volume. As one would expect, the control patients experiencing the exercise paradigm demonstrated a significant increase in hippocampal volume. In the patients with schizophrenia, this was mirrored only in the exercise group; those who played table football failed to show any increase in hippocampal volume.

Here it would have been interesting to have investigated the table football-playing actions in the control patients, as learning coordinated motor skills (without significant physical strain), such as juggling, can increase hippocampal volume in healthy adults (Draganski et al., 2004). Nevertheless, the exercise-induced increase in relative hippocampal volume was clearly apparent in the exercising patients who had schizophrenia. Therefore, it seems likely that the complex physiological response mechanisms required for the translation of physical activity to neuromodulatory effects are still intact even in patients with schizophrenia. At a certain level, the brains of these patients could be considered still relatively healthy and normal.

Schizophrenic patients respond in a unique manner to exercise
To assess the functional integrity of the newly created neurons in the hippocampus, Pajonk et al. studied the ratio of N-acetylaspartate (NAA) to the metabolite creatine (Cr). High N-acetylaspartate levels are often associated with healthy functional neurons and were consistently increased in the exercising patients with schizophrenia. In exercising control patients, the NAA:Cr ratio was relatively unchanged, and some subjects showed a marked reduction. This difference could point to a potentially different mechanism by which patients with schizophrenia increase hippocampal volume compared to control patients who demonstrate the same physiological response to exercise.

Reinforcing the ultrastructural and biochemical effect of exercise upon the schizophrenic hippocampus improved its functional integrity as well. The group with schizophrenia demonstrated a profound increase in short-term memory, while the non-exercising patients with schizophrenia demonstrated a reduction. In addition to proving beneficial for memory function, the exercise paradigm improved schizophrenic symptomology. The non-exercising patients with schizophrenia experienced a worsening of their symptomology.

Physical exercise regimens may improve neurological health in schizophrenic patients
Taken together, these interesting findings indicate that, as with healthy control individuals, the incredibly complex endogenous response mechanism to the strains of exercise is intact and functional in patients with schizophrenia. This excellent news will potentially allow the use of this simple therapeutic paradigm to treat patients with schizophrenia and those with other neurological disorders.

There are likely to be multiple mechanisms by which physical exercise can be translated into improved neurological health. These may include enhanced stress responses, elevation of neurotrophic agents such as brain-derived neurotrophic factor or insulin-like growth factor-1, improvement of cellular metabolism, and angiogenesis. Considerable research has demonstrated that many of these factors are implicated, but in truth the effects of exercise are likely due to a complex interaction of all these factors. It is excellent news that patients with schizophrenia still possess this ability to benefit from the effects of exercise upon the central nervous system.

Potential of pharmacotherapeutics that can mimic exercise
One caveat in this story is familiar to everyone: exercise is a “medicine” that not everyone wants to take. If physical activity were considered a pharmacotherapeutic, it would possess one of the worst compliance rates of any drug. If we could start to understand the endogenous exercise translating mechanisms, we may be able to shortcut the need for many hours at the gym and tap into these mechanisms to enhance the actions of a short jog to those only previously generated by weeks of training (Stranahan et al., 2009).

Even with the potential ability to mimic the effects of exercise, we must remember that these effects do not happen in a simple linear manner. The effects of training are generated by the complex interaction of tens or hundreds of individual factors; if we can start to understand such an intricate interplay between our physiology at rest and during exercise, we may eventually be able to therapeutically exploit this evolutionarily conserved benefit of exercise.

References:

Boyke J, Driemeyer J, Gaser C, Büchel C, May A. Training-induced brain structure changes in the elderly. J Neurosci. 2008 Jul 9;28(28):7031-5. Abstract

Erickson KI, Prakash RS, Voss MW, Chaddock L, Hu L, Morris KS, White SM, Wójcicki TR, McAuley E, Kramer AF. Aerobic fitness is associated with hippocampal volume in elderly humans. Hippocampus. 2009 Oct;19(10):1030-9. Abstract

Pereira AC, Huddleston DE, Brickman AM, Sosunov AA, Hen R, McKhann GM, Sloan R, Gage FH, Brown TR, Small SA. An in vivo correlate of exercise-induced neurogenesis in the adult dentate gyrus. Proc Natl Acad Sci U S A. 2007 Mar 27;104(13):5638-43. Epub 2007 Mar 20. Abstract

Colcombe SJ, Erickson KI, Scalf, PE, Kim JS, Prakash R, McAuley E, Elavsky S, Marquez DX, Hu L, Kramer AF. Aerobic exercise training increases brain volume in aging humans. J Gerontol A Biol Sci Med Sci. 2006;61:1166-70. Abstract

Vaynman S, Gomez-Pinilla F. Revenge of the "sit": how lifestyle impacts neuronal and cognitive health though molecular systems that interface energy metabolism with neuronal plasticity. J Neurosci Res. 2006;84:699–715. Abstract

Karp A, Paillard-Borg S, Wang HX, Silverstein M, Winblad B, Fratiglioni L. Mental, physical, and social components in leisure activities equally contribute to decrease dementia risk. Dement Geriat Cogn Disord. 2006;21:65–73. Abstract

Wilson RS, Mendes De Leon CF, Barnes LL, Schneider JA, Bienias JL, Evans DA, Bennett DA. Participation in cognitively stimulating activities and risk of incident Alzheimer disease. JAMA. 2002;287:742–8. Abstract

Winter B, Breitenstein C, Mooren FC, Voelker K, Fobker M, Lechtermann A, Krueger K, Fromme A, Korsukewitz C, Floel A, Knecht S. High impact running improves learning. Neurobiol Learn Mem. 2007;87:597-609. Abstract

Maudsley S, Martin B, Luttrell LM. G protein-coupled receptor signaling complexity in neuronal tissue: implications for novel therapeutics. Curr Alzheimer Res. 2007 Feb;4(1):3-19. Abstract

Reif A, Fritzen S, Finger M, Strobel A, Lauer M, Schmitt A, Lesch KP. Neural stem cell proliferation is decreased in schizophrenia, but not in depression. Mol Psychiatry. 2006 May;11(5):514-22. Abstract

Draganski B, Gaser C, Busch V, Schuierer G, Bogdahn U, May A. Neuroplasticity: changes in grey matter induced by training. Nature. 2004 Jan 22;427(6972):311-2. Abstract

Stranahan AM, Zhou Y, Martin B, Maudsley S. Pharmacomimetics of exercise: novel approaches for hippocampally-targeted neuroprotective agents. Curr Med Chem. 2009;16(35):4668-78. Abstract

View all comments by Stuart Maudsley

Related News: Thinking Outside the Pillbox: Fish Oil and Exercise for Schizophrenia?

Comment by:  Anthony Hannan
Submitted 19 February 2010
Posted 19 February 2010
  I recommend the Primary Papers

These important new papers (Amminger et al., 2010; Pajonk et al., 2010) suggest interesting approaches for delaying/preventing onset of, and treating, schizophrenia. As the interventions, and cohorts, are very different, it is likely the therapeutic mechanisms are distinct; however, in both cases neurobiological insights may be provided by animal models.

The exercise study (Pajonk et al., 2010) is supported by experimental studies involving environmental manipulations of animal models, which may provide some insight into underlying mechanisms. There is prior evidence, in a knockout mouse model of schizophrenia exhibiting predictive validity, that environmental enrichment (which enhances mental/physical activity levels) from adolescence onwards can ameliorate schizophrenia-like endophenotypes (McOmish et al., 2008). While this model does exhibit hippocampal dysfunction, these mutant mice are also known to have abnormal activity-dependent synapse formation and/or elimination in the postnatal neocortex (Spires et al., 2005), and, therefore, the enhanced mental and physical activity may be inducing its beneficial effects via additional areas outside the hippocampus. In another mouse model of schizophrenia, with a mutation in the neuregulin-1 gene, a minimal form of environmental enrichment provided throughout development can also modulate specific behavioral endophenotypes (Karl et al., 2007).

Environmental enrichment provides opportunities for enhanced sensory, cognitive, and motor activity (exercise), and has been shown to induce beneficial effects in various animal models of neurological and psychiatric disorders (reviewed by Laviola et al., 2008; Sale et al., 2009). Increased physical activity alone has a range of effects, at molecular, cellular, and systems levels, on brain function and cognition (reviewed by Cotman et al., 2007; Hillman et al., 2008). While Pajonk et al. (2010) have identified the hippocampus as a region of interest, enhanced exercise clearly has the potential to induce beneficial effects via additional systems outside the hippocampus. One key aspect of applying these environmental interventions in valid animal models is that we might identify the molecular/cellular mechanisms mediating the beneficial effects, and thus pave the way for the development and optimization of new therapeutic approaches.

References:

Amminger GP, Schäfer MR, Papageorgiou K, Klier CM, Cotton SM, Harrigan SM, Mackinnon A, McGorry PD, Berger GE. Long-chain Ω-3 fatty acids for indicated prevention of psychotic disorders: A randomized, placebo-controlled trial. Arch Gen Psychiatry. 2010 Feb;67(2):146-54. Abstract

Cotman CW, Berchtold NC, Christie LA. Exercise builds brain health: key roles of growth factor cascades and inflammation. Trends Neurosci. 2007 Sep;30(9):464-72. Abstract

Hillman CH, Erickson KI, Kramer AF. Be smart, exercise your heart: exercise effects on brain and cognition. Nat Rev Neurosci. 2008 Jan;9(1):58-65. Abstract

Karl T, Duffy L, Scimone A, Harvey RP, Schofield PR. Altered motor activity, exploration and anxiety in heterozygous neuregulin 1 mutant mice: implications for understanding schizophrenia. Genes Brain Behav. 2007 Oct;6(7):677-87. Abstract

Laviola G, Hannan AJ, Macrě S, Solinas M, Jaber M. Effects of enriched environment on animal models of neurodegenerative diseases and psychiatric disorders. Neurobiol Dis. 2008 Aug;31(2):159-68. Abstract

McOmish CE, Burrows E, Howard M, Scarr E, Kim D, Shin HS, Dean B, van den Buuse M, Hannan AJ. Phospholipase C-beta1 knockout mice exhibit endophenotypes modeling schizophrenia which are rescued by environmental enrichment and clozapine administration. Mol Psychiatry. 2008 Jul;13(7):661-72. Abstract

Pajonk F-G, Wobrock T, Gruber O, Scherk H, Berner D, Kaizl I, Kierer A, Müller S, Oest M, Meyer T, Backens M, Schneider-Axmann T, Thornton AE, Honer WG, Falkai P. Hippocampal plasticity in response to exercise in schizophrenia. Arch Gen Psychiatry. 2010 Feb;67(2):133-43. Abstract

Sale A, Berardi N, Maffei L. Enrich the environment to empower the brain. Trends Neurosci. 2009 Apr;32(4):233-9. Abstract

Spires TL, Molnár Z, Kind PC, Cordery PM, Upton AL, Blakemore C, Hannan AJ. Activity-dependent regulation of synapse and dendritic spine morphology in developing barrel cortex requires phospholipase C-beta1 signalling. Cereb Cortex. 2005 Apr;15(4):385-93. Abstract

View all comments by Anthony Hannan