Preface

Modern societies have recently experienced several transitions in dietary habits. The last few centuries have emerged from famine by increasing the consumption of cereals. Also, food production has been industrialized, which enhances the diversity of food products. However, food industrialization also induces a rise in saturated fats and sugars in the diet, paralleled by a reduction in physical activity. More developed countries are now in a new transition phase fueled by the desire for healthier and less processed food. With these dietary transitions, human health has evolved, following the famous adage "We are what we eat." The most obvious example is the important escalation in diabetes occurrence over the last 30 years or so. Therefore, nutrition is a critical environmental factor modulating health throughout life.

Over the past decades, scientific interest has been focused on the impact of nutrition specifically on brain function. Several years of research have established that nutrients such as polyunsaturated fatty acids, vitamins, polyphenols, essential amino acids, and sugar are the basis for brain function and their imbalance can cause or precipitate brain dysfunction.

Most nutrients can cross the blood–brain barrier to impact brain physiology. Nutrients in the brain can either fuel brain cells, contribute to tissue architecture, or initiate signaling pathways through their derivatives. Nutrients ultimately participate in brain development, cognitive and emotional behaviors, and can influence the susceptibility to develop brain pathologies. Despite the huge amount of knowledge brought about by the scientific community, a lot still needs to be unraveled.

Beyond dietary habits, nutrients can also be isolated and formulated to serve as therapeutic agents. Indeed, they are less prone to develop secondary effects than pharmaceuticals since the organism has the machinery to metabolize them. In addition, they can enter the brain more easily than synthetic molecules, which is essential to reach therapeutic efficacy for brain-related disorders.

More recently, the field of brain nutrition has been enlarged by considering bidirectional interactions between the brain and the periphery, including microbiota and the enteric system. For example, some microbiota species release derivatives following digestion and can have a direct effect on brain function. In the other direction, it is now clear that the brain can control digestion and metabolism, not only through the hypothalamus, but also through mechanisms and circuits that are highly sophisticated, which delay their precise understanding. In addition, these bidirectional interactions between the brain and the periphery for nutrition are interdependent, which further complicates the picture.

*Feed Your Mind: How Does Nutrition Modulate Brain Function throughout Life?* is a selection of current research on the impact of diet on brain function. The book is organized into five chapters, opening with the editor's Introductory chapter.

Chapter 2 is dedicated to the role of lipids in the brain. In particular, polyunsaturated fatty acids are highly enriched in the brain and brain cells. This chapter

focuses on these polyunsaturated fatty acids and their derivatives, involved in the resolution of neuroinflammation.

Chapter 3 focuses on the role of glucose in fueling the brain, and how some hypothalamic neurons are sensitive to glycemia, to participate in its regulation. Indeed, the brain represents approximately 2% of body weight but consumes approximately 20% of its total energy. Therefore, blood glucose is essential for brain function. This chapter also discusses the role of fructose in brain function, since the current industrialized diet contains abnormally high levels of fructose.

Chapter 4 presents the concept of autophagy and how nutrition can modulate it. Autophagy is a process of protein degradation in cells that allow control of cell integrity. Autophagy is stimulated by caloric restriction; however, the global trend in industrialized countries is toward calories over consumption. Therefore, this chapter presents how modern dietary habits can favor neuropathologies associated with autophagy defects, such as in Alzheimer's disease.

Finally, Chapter 5 concentrates on brain–gut interactions in the context of enteral feeding. Some chronic pathologies require non-oral feeding, which basically bypasses the brain in the control of feeding. This particular situation highlights the role of the brain in different steps of feeding, from appetite to digestion. This chapter also points out strategies to improve digestion in enteral feeding.

We would like to thank all the authors for their valuable contributions and for their constructive interplay throughout the editorial process.

> **Clémentine Bosch-Bouju, Sophie Layé and Véronique Pallet** NutriNeuro Lab UMR1286, INRA/Bordeaux University/Bordeaux INP, France

> > **1**

Section 1

Introduction

Section 1 Introduction

**3**

**Chapter 1**

Introductory Chapter: Feed Your

Nutrition is a transdisciplinary science that aims at studying the role of food and physical exercise on health and diseases. It includes notably biochemistry, metabolism, behavioural and social studies. Nutrition science is highly diverse and

• The control of energy balance is a primary need for humans and for all ani-

related to the diversity of culture, even in one single country.

industrialisation has engendered a profound dietary imbalance.

obesity, cardiovascular disorders and depressive disorders.

• In human societies, alimentation participates to social behaviour.

• A high diversity of dietary models throughout the world exists, which is closely

• Modern societies have been hugely transformed since food industrialization.

The last point has critically changed the way of life for people in industrialised countries. Food industrialisation was originally designed to ease life and feed the growing population following the First and Second World Wars. Unexpectedly,

For the first time in history, people with industrialised diet are facing food with high quantities of sugar and saturated fats. This diet can also lead to deficiency in essential nutrients, such as vitamins, minerals and polyunsaturated fatty acids. This change in diet has been paralleled by an increase in sedentariness, which contributes to energy imbalance. This change in the last 70 years leads to global epidemics as

In this context, the brain appears as a structure highly sensitive to dietary imbalance [1]. In addition, the brain can participate to dietary imbalance by controlling feeding behaviours and through its interaction with peripheral organs and hormones involved in the control of energy balance. Thus, the impact of nutrition on brain function is a specific field of research that has gain interest in the recent years, and the role of the brain appears central in nutrition. Nutrition will impact the brain from early-developmental stages to adolescence, when the brain tissue is built and modelled. Nutrition also appears critical at adult age, to maintain optimal brain function. Finally, nutrition appears as an important environmental factor that

Mind - How Does Nutrition

Modulate Brain Function

throughout Life?

constantly evolving for several reasons:

mals, which implies it is of high importance.

*Clémentine Bosch-Bouju*

**1. Introduction**

## **Chapter 1**

## Introductory Chapter: Feed Your Mind - How Does Nutrition Modulate Brain Function throughout Life?

*Clémentine Bosch-Bouju*

## **1. Introduction**

Nutrition is a transdisciplinary science that aims at studying the role of food and physical exercise on health and diseases. It includes notably biochemistry, metabolism, behavioural and social studies. Nutrition science is highly diverse and constantly evolving for several reasons:


The last point has critically changed the way of life for people in industrialised countries. Food industrialisation was originally designed to ease life and feed the growing population following the First and Second World Wars. Unexpectedly, industrialisation has engendered a profound dietary imbalance.

For the first time in history, people with industrialised diet are facing food with high quantities of sugar and saturated fats. This diet can also lead to deficiency in essential nutrients, such as vitamins, minerals and polyunsaturated fatty acids. This change in diet has been paralleled by an increase in sedentariness, which contributes to energy imbalance. This change in the last 70 years leads to global epidemics as obesity, cardiovascular disorders and depressive disorders.

In this context, the brain appears as a structure highly sensitive to dietary imbalance [1]. In addition, the brain can participate to dietary imbalance by controlling feeding behaviours and through its interaction with peripheral organs and hormones involved in the control of energy balance. Thus, the impact of nutrition on brain function is a specific field of research that has gain interest in the recent years, and the role of the brain appears central in nutrition. Nutrition will impact the brain from early-developmental stages to adolescence, when the brain tissue is built and modelled. Nutrition also appears critical at adult age, to maintain optimal brain function. Finally, nutrition appears as an important environmental factor that should be controlled through ageing, to prevent neurodegenerative processes. In this introductory chapter, we will take the example of vitamin A, which is a nutrient that has been demonstrated as critical for brain function throughout life [2–5].

### **2. Vitamin A and its active metabolite: retinoic acid**

Vitamin A is a lipophilic vitamin that cannot be synthesised de novo by organism. Food sources are animal products for the preformed vitamin A and vegetables for provitamin A. Preformed vitamin A and provitamin A are found in sufficient quantities in most diets, but strong deficiency may occur in undernourished populations, mainly in sub-Saharan Africa. Vitamin A deficiency in children can cause blindness and growth retardation and can ultimately lead to death. Besides, vitamin A deficiency may occur with ageing, since its bioavailability can be reduced. In both cases, vitamin A supplementation can reverse this deficiency, which emphasises the need to study the impact of vitamin A supplementation for pregnant women and children, as well as for elderly.

The active metabolite of vitamin A in the brain is the all-*trans* retinoic acid (a*t*RA), synthesised from vitamin A (retinol) by aldehyde dehydrogenase enzymes [6, 7]. Retinoic acid and its derivatives bind to nuclear receptors, namely, RAR and RXR. These receptors act as homo- or heterodimers to control gene transcription [3, 6]. Therefore, retinoic acid is a powerful morphogen factor, highly involved in embryonic development and growth [8].

### **3. The role of vitamin A during brain development**

During brain development, retinoic acid synthesised from dietary vitamin A binds to nuclear receptors to drive transcription of hundreds of genes. Retinoic acid is a morphogen that acts through a concentration gradient [8]. To carry out the precision of retinoic acid gradient during embryonic development, metabolism and signalling pathways for retinoic acid are multiple and highly robust [8]. Remarkably, retinoic acid is the only morphogen that comes from dietary sources, which highlights the importance of vitamin A intake during pregnancy. Through its action on nuclear receptors, retinoic acid is implicated in the patterning of neural axis along the dorsoventral and anteroposterior axes [2].

In addition to development and growth, retinoic acid in the brain is critical for neuronal differentiation and neurite outgrowth. This is particularly true in the basal ganglia network, which is a group of brain structures involved in the control of action. Indeed, retinoic acid is key in the differentiation of specific subpopulations of neurons, such as the medium size spiny neurons in the striatum, or the dopaminergic neurons from the substantia nigra pars compacta [9–13].

#### **4. The role of vitamin A in the adult brain**

At adult age, vitamin A-derived retinoic acid has two remarkable roles; it is involved in homeostatic plasticity and in neurogenesis [3, 5, 14, 15]. First, retinoic acid induces molecular and morphological changes in neuronal network, to maintain overall synaptic activity constant, despite synaptic plasticity, a process named homeostatic synaptic plasticity [16]. For this, retinoic acid binds to nuclear RAR and RXR receptors, but evidence suggests that non-genomic mechanisms are also

**5**

disease.

**6. Conclusion**

*Introductory Chapter: Feed Your Mind - How Does Nutrition Modulate Brain Function…*

involved [17–19]. Changes induced by retinoic acid to produce homeostatic plasticity include transcription of synaptic proteins, such as AMPA receptors, but also modulation of neuronal morphology, through outgrowth or retraction of synapse

Second, retinoic acid controls neurogenesis. In rodent deficient for vitamin A, neurogenesis in the hippocampus is strongly dampened and can be restored by replenishment with vitamin A or derivatives [20–23]. However, in physiological conditions, retinoic acid applied exogenously can inhibit neurogenesis in the hippocampus and facilitate cell differentiation [3]. The apparent discrepancy between physiological and deficient states may be explained by the finely tuned concentration and timing of retinoic acid that is needed for its control of neurogenesis. In the hypothalamus, neurogenesis is highly dynamic to orchestrate circadian rhythms that govern several hypothalamic functions. In this structure, a similar role has been demonstrated for retinoic acid, inhibiting proliferation of cells and thus neurogenesis [5].

Ageing process is a physiological and unavoidable phenomenon involving the whole body. Related to brain function, ageing is characterised by a cognitive decline, which comprises all molecular and cellular alterations that lead ultimately to decreased performance in cognitive and executive functions [24]. Evidence suggests that bioavailability of retinoic acid in the brain reduces with ageing, likely due to peripheral alterations [4]. Yet several studies have highlighted the parallel between ageing, decrease in brain retinoid signalling and cognitive decline [4, 25–27]. Mechanisms linking retinoid metabolism and cognitive decline are not yet completely unravelled, but evidence suggests the involvement of glucocorticoids

[20] and morphological changes of neuronal trees (unpublished data).

Beyond normal ageing, decreased retinoid signalling in the brain with ageing may be involved in neurodegenerative processes, such as in Alzheimer's and Parkinson's diseases. For Alzheimer's disease, accumulating evidence suggests that the lack of retinoic acid in the hippocampus is a risk factor that precipitates the deposition of β-amyloid plaques, a histological landmark of the disease [28–31]. Therefore, vitamin A and retinoids appear as potential therapeutics [30, 32]. However, mechanisms are not yet sufficiently understood to elaborate such therapeutics. Additionally, retinoids are lipophilic molecules that oxidise rapidly, which

In the context of Parkinson's disease, a similar process has been proposed. Reduced signalling of retinoids in the brain, and particularly in the substantia nigra compacta, may be a risk factor that accelerates the degeneration of dopaminergic neurons [33, 34]. This hypothesis is supported by the fact that rodents deficient for vitamin A or for retinoid receptors display motor impairments close to Parkinson's models [35, 36]. Some studies revealed encouraging results with retinoid supplementation to prevent neurodegeneration in cell culture or in vivo [37, 38], but research is still to preliminary to envisage soon vitamin A-based treatments for this

Through the solely example of vitamin A, we can appreciate the importance of nutrition for brain physiology, from development to adult age. Remarkably, a same

*DOI: http://dx.doi.org/10.5772/intechopen.89349*

**5. The role of vitamin A in the ageing brain**

render their pharmacological use challenging.

boutons and dendrites.

*Introductory Chapter: Feed Your Mind - How Does Nutrition Modulate Brain Function… DOI: http://dx.doi.org/10.5772/intechopen.89349*

involved [17–19]. Changes induced by retinoic acid to produce homeostatic plasticity include transcription of synaptic proteins, such as AMPA receptors, but also modulation of neuronal morphology, through outgrowth or retraction of synapse boutons and dendrites.

Second, retinoic acid controls neurogenesis. In rodent deficient for vitamin A, neurogenesis in the hippocampus is strongly dampened and can be restored by replenishment with vitamin A or derivatives [20–23]. However, in physiological conditions, retinoic acid applied exogenously can inhibit neurogenesis in the hippocampus and facilitate cell differentiation [3]. The apparent discrepancy between physiological and deficient states may be explained by the finely tuned concentration and timing of retinoic acid that is needed for its control of neurogenesis. In the hypothalamus, neurogenesis is highly dynamic to orchestrate circadian rhythms that govern several hypothalamic functions. In this structure, a similar role has been demonstrated for retinoic acid, inhibiting proliferation of cells and thus neurogenesis [5].

## **5. The role of vitamin A in the ageing brain**

Ageing process is a physiological and unavoidable phenomenon involving the whole body. Related to brain function, ageing is characterised by a cognitive decline, which comprises all molecular and cellular alterations that lead ultimately to decreased performance in cognitive and executive functions [24]. Evidence suggests that bioavailability of retinoic acid in the brain reduces with ageing, likely due to peripheral alterations [4]. Yet several studies have highlighted the parallel between ageing, decrease in brain retinoid signalling and cognitive decline [4, 25–27]. Mechanisms linking retinoid metabolism and cognitive decline are not yet completely unravelled, but evidence suggests the involvement of glucocorticoids [20] and morphological changes of neuronal trees (unpublished data).

Beyond normal ageing, decreased retinoid signalling in the brain with ageing may be involved in neurodegenerative processes, such as in Alzheimer's and Parkinson's diseases. For Alzheimer's disease, accumulating evidence suggests that the lack of retinoic acid in the hippocampus is a risk factor that precipitates the deposition of β-amyloid plaques, a histological landmark of the disease [28–31]. Therefore, vitamin A and retinoids appear as potential therapeutics [30, 32]. However, mechanisms are not yet sufficiently understood to elaborate such therapeutics. Additionally, retinoids are lipophilic molecules that oxidise rapidly, which render their pharmacological use challenging.

In the context of Parkinson's disease, a similar process has been proposed. Reduced signalling of retinoids in the brain, and particularly in the substantia nigra compacta, may be a risk factor that accelerates the degeneration of dopaminergic neurons [33, 34]. This hypothesis is supported by the fact that rodents deficient for vitamin A or for retinoid receptors display motor impairments close to Parkinson's models [35, 36]. Some studies revealed encouraging results with retinoid supplementation to prevent neurodegeneration in cell culture or in vivo [37, 38], but research is still to preliminary to envisage soon vitamin A-based treatments for this disease.

### **6. Conclusion**

Through the solely example of vitamin A, we can appreciate the importance of nutrition for brain physiology, from development to adult age. Remarkably, a same

*Feed Your Mind - How Does Nutrition Modulate Brain Function throughout Life?*

**2. Vitamin A and its active metabolite: retinoic acid**

children, as well as for elderly.

embryonic development and growth [8].

**3. The role of vitamin A during brain development**

axis along the dorsoventral and anteroposterior axes [2].

**4. The role of vitamin A in the adult brain**

nergic neurons from the substantia nigra pars compacta [9–13].

should be controlled through ageing, to prevent neurodegenerative processes. In this introductory chapter, we will take the example of vitamin A, which is a nutrient that has been demonstrated as critical for brain function throughout life [2–5].

Vitamin A is a lipophilic vitamin that cannot be synthesised de novo by organism. Food sources are animal products for the preformed vitamin A and vegetables for provitamin A. Preformed vitamin A and provitamin A are found in sufficient quantities in most diets, but strong deficiency may occur in undernourished populations, mainly in sub-Saharan Africa. Vitamin A deficiency in children can cause blindness and growth retardation and can ultimately lead to death. Besides, vitamin A deficiency may occur with ageing, since its bioavailability can be reduced. In both cases, vitamin A supplementation can reverse this deficiency, which emphasises the need to study the impact of vitamin A supplementation for pregnant women and

The active metabolite of vitamin A in the brain is the all-*trans* retinoic acid (a*t*RA), synthesised from vitamin A (retinol) by aldehyde dehydrogenase enzymes [6, 7]. Retinoic acid and its derivatives bind to nuclear receptors, namely, RAR and RXR. These receptors act as homo- or heterodimers to control gene transcription [3, 6]. Therefore, retinoic acid is a powerful morphogen factor, highly involved in

During brain development, retinoic acid synthesised from dietary vitamin A binds to nuclear receptors to drive transcription of hundreds of genes. Retinoic acid is a morphogen that acts through a concentration gradient [8]. To carry out the precision of retinoic acid gradient during embryonic development, metabolism and signalling pathways for retinoic acid are multiple and highly robust [8]. Remarkably, retinoic acid is the only morphogen that comes from dietary sources, which highlights the importance of vitamin A intake during pregnancy. Through its action on nuclear receptors, retinoic acid is implicated in the patterning of neural

In addition to development and growth, retinoic acid in the brain is critical for neuronal differentiation and neurite outgrowth. This is particularly true in the basal ganglia network, which is a group of brain structures involved in the control of action. Indeed, retinoic acid is key in the differentiation of specific subpopulations of neurons, such as the medium size spiny neurons in the striatum, or the dopami-

At adult age, vitamin A-derived retinoic acid has two remarkable roles; it is involved in homeostatic plasticity and in neurogenesis [3, 5, 14, 15]. First, retinoic acid induces molecular and morphological changes in neuronal network, to maintain overall synaptic activity constant, despite synaptic plasticity, a process named homeostatic synaptic plasticity [16]. For this, retinoic acid binds to nuclear RAR and RXR receptors, but evidence suggests that non-genomic mechanisms are also

**4**

nutrient can have different roles depending on the timing, the brain structure and even the cell type. The field of research on nutrition applied to neurosciences is growing, to better encompass the impact of industrialised diet on brain function and also to consider nutrients and their derivatives as potential therapeutic strategies. In this way, it is to expect that nutritional approaches will give rise in the future to new therapeutics to prevent, and in some case cure, neurological disorders.

## **Author details**

Clémentine Bosch-Bouju INRA, Bordeaux INP, NutriNeuro, University of Bordeaux, Bordeaux, France

\*Address all correspondence to: clementine.bosch-bouju@inra.fr

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**7**

*Introductory Chapter: Feed Your Mind - How Does Nutrition Modulate Brain Function…*

Opinion in Genetics and Development.

[10] Occhi G, Regazzo D, Albiger NM, Ceccato F, Ferasin S, Scanarini M, et al. Activation of the dopamine receptor Type-2 (DRD2) promoter by 9-cis retinoic acid in a cellular model of Cushing's disease mediates the inhibition of cell proliferation and ACTH secretion without a complete corticotroph-to-melanotroph transdifferentiation. Endocrinology.

[11] Pedrini S, Bogush A, Ehrlich ME. Phosphatidylinositide 3-kinase and protein kinase C zeta mediate retinoic acid induction of DARPP-32 in medium size spiny neurons in vitro. Journal of Neurochemistry. 2008;**106**(2):917-924

[12] Podleśny-Drabiniok A, Sobska J, de Lera AR, Gołembiowska K, Kamińska K, Dollé P, et al. Distinct retinoic acid receptor (RAR) isotypes control

differentiation of embryonal carcinoma cells to dopaminergic or striatopallidal medium spiny neurons. Scientific

[13] Rataj-Baniowska M, Niewiadomska-Cimicka A, Paschaki M, Szyszka-Niagolov M, Carramolino L, Torres M, et al. Retinoic acid receptor β controls development of Striatonigral projection neurons through FGF-dependent and Meis1-dependent mechanisms. Journal of Neuroscience: The Official Journal of the Society for Neuroscience.

[14] Lane MA, Bailey SJ. Role of retinoid signalling in the adult brain. Progress in Neurobiology. 2005;**75**(4):275-293

Reports. 2017;**7**(1):13671

2015;**35**(43):14467-14475

[9] Chatzi C, Brade T, Duester G. Retinoic acid functions as a key GABAergic differentiation signal in the basal ganglia. PLoS Biology.

2012;**22**(6):562-569

2011;**9**(4):e1000609

2014;**155**(9):3538-3549

*DOI: http://dx.doi.org/10.5772/intechopen.89349*

[1] Gómez-Pinilla F. Brain foods: The effects of nutrients on brain function. Nature Reviews. Neuroscience.

[2] Maden M. Retinoic acid in the development, regeneration and maintenance of the nervous system. Nature Reviews. Neuroscience.

[3] McCaffery P, Zhang J, Crandall JE. Retinoic acid signaling and function in the adult hippocampus. Journal of Neurobiology. 2006;**66**(7):780-791

[4] Sauvant P,Feart C, Sauvant J, Pallet V. Vitamin A and cognitive impairment. In: Diet and Nutrition in Dementia and Cognitive Decline. Advances in Clinical Neuroscience and Rehabilitation; 2015. pp. 623- 635. Available from: https://

linkinghub.elsevier.com/retrieve/pii/

[5] Shearer KD, Stoney PN, Morgan PJ, McCaffery PJ. A vitamin for the brain. Trends in Neurosciences.

[6] Blomhoff R, Blomhoff HK. Overview

B9780124078246000586

2012;**35**(12):733-741

2006;**66**(7):606-630

2012;**64**(3):520-539

of retinoid metabolism and function. Journal of Neurobiology.

[7] Koppaka V, Thompson DC, Chen Y, Ellermann M, Nicolaou KC,

pharmacology, mechanism of action, substrate specificity, and clinical application. The American Society for Pharmacology and Experimental Therapeutics. Pharmacological Reviews.

[8] Schilling TF, Nie Q, Lander AD. Dynamics and precision in retinoic acid morphogen gradients. Current

Juvonen RO, et al. Aldehyde dehydrogenase inhibitors: A comprehensive review of the

**References**

2008;**9**(7):568-578

2007;**8**(10):755-765

*Introductory Chapter: Feed Your Mind - How Does Nutrition Modulate Brain Function… DOI: http://dx.doi.org/10.5772/intechopen.89349*

## **References**

*Feed Your Mind - How Does Nutrition Modulate Brain Function throughout Life?*

nutrient can have different roles depending on the timing, the brain structure and even the cell type. The field of research on nutrition applied to neurosciences is growing, to better encompass the impact of industrialised diet on brain function and also to consider nutrients and their derivatives as potential therapeutic strategies. In this way, it is to expect that nutritional approaches will give rise in the future to new therapeutics to prevent, and in some case cure, neurological disorders.

**6**

**Author details**

Clémentine Bosch-Bouju

provided the original work is properly cited.

INRA, Bordeaux INP, NutriNeuro, University of Bordeaux, Bordeaux, France

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

\*Address all correspondence to: clementine.bosch-bouju@inra.fr

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[2] Maden M. Retinoic acid in the development, regeneration and maintenance of the nervous system. Nature Reviews. Neuroscience. 2007;**8**(10):755-765

[3] McCaffery P, Zhang J, Crandall JE. Retinoic acid signaling and function in the adult hippocampus. Journal of Neurobiology. 2006;**66**(7):780-791

[4] Sauvant P,Feart C, Sauvant J, Pallet V. Vitamin A and cognitive impairment. In: Diet and Nutrition in Dementia and Cognitive Decline. Advances in Clinical Neuroscience and Rehabilitation; 2015. pp. 623- 635. Available from: https:// linkinghub.elsevier.com/retrieve/pii/ B9780124078246000586

[5] Shearer KD, Stoney PN, Morgan PJ, McCaffery PJ. A vitamin for the brain. Trends in Neurosciences. 2012;**35**(12):733-741

[6] Blomhoff R, Blomhoff HK. Overview of retinoid metabolism and function. Journal of Neurobiology. 2006;**66**(7):606-630

[7] Koppaka V, Thompson DC, Chen Y, Ellermann M, Nicolaou KC, Juvonen RO, et al. Aldehyde dehydrogenase inhibitors: A comprehensive review of the pharmacology, mechanism of action, substrate specificity, and clinical application. The American Society for Pharmacology and Experimental Therapeutics. Pharmacological Reviews. 2012;**64**(3):520-539

[8] Schilling TF, Nie Q, Lander AD. Dynamics and precision in retinoic acid morphogen gradients. Current Opinion in Genetics and Development. 2012;**22**(6):562-569

[9] Chatzi C, Brade T, Duester G. Retinoic acid functions as a key GABAergic differentiation signal in the basal ganglia. PLoS Biology. 2011;**9**(4):e1000609

[10] Occhi G, Regazzo D, Albiger NM, Ceccato F, Ferasin S, Scanarini M, et al. Activation of the dopamine receptor Type-2 (DRD2) promoter by 9-cis retinoic acid in a cellular model of Cushing's disease mediates the inhibition of cell proliferation and ACTH secretion without a complete corticotroph-to-melanotroph transdifferentiation. Endocrinology. 2014;**155**(9):3538-3549

[11] Pedrini S, Bogush A, Ehrlich ME. Phosphatidylinositide 3-kinase and protein kinase C zeta mediate retinoic acid induction of DARPP-32 in medium size spiny neurons in vitro. Journal of Neurochemistry. 2008;**106**(2):917-924

[12] Podleśny-Drabiniok A, Sobska J, de Lera AR, Gołembiowska K, Kamińska K, Dollé P, et al. Distinct retinoic acid receptor (RAR) isotypes control differentiation of embryonal carcinoma cells to dopaminergic or striatopallidal medium spiny neurons. Scientific Reports. 2017;**7**(1):13671

[13] Rataj-Baniowska M, Niewiadomska-Cimicka A, Paschaki M, Szyszka-Niagolov M, Carramolino L, Torres M, et al. Retinoic acid receptor β controls development of Striatonigral projection neurons through FGF-dependent and Meis1-dependent mechanisms. Journal of Neuroscience: The Official Journal of the Society for Neuroscience. 2015;**35**(43):14467-14475

[14] Lane MA, Bailey SJ. Role of retinoid signalling in the adult brain. Progress in Neurobiology. 2005;**75**(4):275-293

[15] Olson CR, Mello CV. Significance of vitamin A to brain function, behavior and learning. Molecular Nutrition and Food Research. 2010;**54**(4):489-495

[16] Turrigiano GG, Nelson SB. Homeostatic plasticity in the developing nervous system. Nature Reviews. Neuroscience. 2004;**5**(2):97-107

[17] Aoto J, Nam CI, Poon MM, Ting P, Chen L. Synaptic signaling by alltrans retinoic acid in homeostatic synaptic plasticity. Neuron. 2008;**60**(2):308-320

[18] Arendt KL, Zhang Y, Jurado S, Malenka RC, Südhof TC, Chen L. Retinoic acid and LTP recruit postsynaptic AMPA receptors using distinct SNARE-dependent mechanisms. Neuron. 2015;**86**(2):442-456

[19] Chen L, Lau AG, Sarti F. Synaptic retinoic acid signaling and homeostatic synaptic plasticity. Neuropharmacology. 2014;**78**:3-12

[20] Bonhomme D, Minni AM, Alfos S, Roux P, Richard E, Higueret P, et al. Vitamin A status regulates glucocorticoid availability in Wistar rats: Consequences on cognitive functions and hippocampal neurogenesis? Frontiers in Behavioral Neuroscience. 2014;**20**:1-13

[21] Bonnet E, Touyarot K, Alfos S, Pallet V, Higueret P, Abrous DN. Retinoic acid restores adult hippocampal neurogenesis and reverses spatial memory deficit in vitamin A deprived rats. In: McCabe BD, editor. PLoS One. 2008;**3**(10):e3487

[22] Jacobs S, Lie DC, DeCicco KL, Shi Y, DeLuca LM, Gage FH, et al. Retinoic acid is required early during adult neurogenesis in the dentate gyrus. Proceedings of the National Academy of Sciences of the United States of America. 2006;**103**(10):3902-3907

[23] Touyarot K, Bonhomme D, Roux P, Alfos S, Lafenêtre P, Richard E, et al. A mid-life vitamin A supplementation prevents age-related spatial memory deficits and hippocampal neurogenesis alterations through CRABP-I. PLoS One. 2013;**8**(8):e72101

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[25] Bonhomme D, Pallet V, Dominguez G, Servant L, Henkous N, Lafenêtre P, et al. Retinoic acid modulates intrahippocampal levels of corticosterone in middle-aged mice: Consequences on hippocampal plasticity and contextual memory. Frontiers in Aging Neuroscience. 2014;**6**:6

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[27] Mingaud F, Mormede C, Etchamendy N, Mons N, Niedergang B, Wietrzych M, et al. Retinoid hyposignaling contributes to aging-related decline in hippocampal function in short-term/working memory organization and long-term declarative memory encoding in mice. Journal of Neuroscience: The Official Journal of the Society for Neuroscience. 2008;**28**(1):279-291

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**9**

*Introductory Chapter: Feed Your Mind - How Does Nutrition Modulate Brain Function…*

[37] Esteves M, Cristóvão AC, Saraiva T, Rocha SM, Baltazar G, Ferreira L, et al.

nanoparticles induce neuroprotection in a mouse model for Parkinson's disease. Frontiers in Aging Neuroscience.

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**8**

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[31] Goodman AB, Pardee AB. Evidence for defective retinoid transport and function in late onset Alzheimer's disease. Proceedings of the National Academy of Sciences of the United States of America. 2003;**100**(5):2901-2905

[32] Sodhi RK, Singh N. Retinoids as potential targets for Alzheimer's disease. Pharmacology, Biochemistry, and Behavior. 2014;**120**:117-123

[33] Cai H, Liu G, Sun L, Ding J. Aldehyde dehydrogenase 1 making molecular inroads into the differential vulnerability of nigrostriatal dopaminergic neuron subtypes in Parkinson's disease. Translational Neurodegeneration. 2014;**3**:27

[34] Liu G, Yu J, Ding J, Xie C, Sun L, Rudenko I, et al. Aldehyde dehydrogenase 1 defines and protects a nigrostriatal dopaminergic neuron subpopulation. The Journal of Clinical Investigation. 2014;**124**(7):3032-3046

[35] Carta M, Stancampiano R, Tronci E, Collu M, Usiello A, Morelli M, et al. Vitamin A deficiency induces motor impairments and striatal cholinergic dysfunction in rats. Neuroscience. 2006;**139**(4):1163-1172

[36] Krezel W, Ghyselinck N, Samad TA, Dupé V, Kastner P, Borrelli E, et al. Impaired locomotion and dopamine signaling in retinoid receptor mutant mice. Science. 1998;**279**(5352):863-867

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[38] Reiner DJ, Yu S-J, Shen H, He Y, Bae E, Wang Y. 9-cis retinoic acid protects against methamphetamineinduced neurotoxicity in nigrostriatal dopamine neurons. Neurotoxicity Research. 2014;**25**(3):248-261

**11**

Section 2

PUFA Metabolism

in the Brain

Section 2
