Although DNA methylation has long been regarded as a static and irreversible process, studies begin to accumulate that demonstrate that both DNA methylation as well as DNA demethylation can be rapidly and transiently induced, not only in an early developmental phase, but also in the adult brain (Blomen and Boonstra, 2011;Weaver et al., 2005). So far we have reviewed the molecular mechanisms of brain plasticity, and how stress can cause epigenetic alterations in BDNF expression, which increases the individual susceptibility to a variety of psychiatric illnesses. However, when these epigenetic changes are reversible, treatment methods which specifically target to reverse these maladaptive epigenetic changes might offer a promising future for many hard-to-cure diseases and disorders.
While downregulation of BDNF is associated with decreased brain plasticity and increased psychopathology, upregulating BDNF might be an essential part in treatment of psychiatric disorder. There are indeed studies indicating that upregulating BDNF is associated with an increased response to treatment (Kobayashi, 2005). And although the exact mechanism remain not fully understood, increased expression of BDNF is regarded as an important mediator of the effect of anti-depressive medications (Castrén and Rantamäki T., 2010).
PTSD and other stress-induced psychiatric disorders are an example of how environmental stimuli can modulate and alter the human brain structure and function in a profound way. As we have discussed, these changes are in some studies demonstrated to correlate with decreased BDNF expression due epigenetic changes. We propose that environmental or behavioral factors have the potential to reverse these maladaptive genetic alterations as well, resulting in an increase in BDNF secretion and expression. Besides the ability of exerting strong detrimental effects, modulation of BDNF by the environment can also support structural and functional alterations in the brain in such ways to promote health and stability.
There are a wide variety of factors which have been found to regulate BDNF gene expression, including dietary factors (Fontn-Lozano et al., 2008;Mattson et al., 2003), stress (Calabrese et al., 2009), reactive oxygen species (ROS) (Lee et al., 2009), ambient light (Karpova et al., 2010;Lee et al., 2009)), physical exercise (Gomez-Pinilla et al., 2008;Kempermann et al., 2010b), sleep (Hairston et al., 2004), environmental enrichment (Beauquis et al., 2010;Guilarte et al., 2003) and social enrichment (Branchi et al., 2006;Branchi, 2009;Curley et al., 2009;D'Andrea et al., 2010). In this chapter we will attempt to briefly review the most significant behavioral and environmental factors that have currently been demonstrated to modulate BDNF expression and neuronal plasticity. Out of these findings, implications for treatment methods can be discussed in the following chapters.
Neuronal plasticity is activity-dependent
One of the key features of synaptic plasticity is its 'input-specificity' or 'synapse-specificity', which means that synaptic modifications occur only at synapses that experience changes in neural activity (Nagappan, 2005;West, 2008). This activity-dependent cooperative selection of simultaneously active neurons is considered to be a central and critical feature in the development of functional neural networks, as well as in the elimination of inactive and incoherent neuronal contacts (Poo, 2001;West, 2008). Norman Doidge, in his book The Brain that Changes Itselves, calls this the Use-it-or-loose-it principle of the brain (Norman Doidge, 2007).
The cytoplasmic calcium influx induced by synaptic activation triggers calcium-dependent signaling cascades that regulate BDNF gene expression through the activation of specific transcription factors (Kolarow et al., 2007;Tao et al., 2002;West et al., 2001). Also, NTFs are released from the pre-synaptic vesicles on a calcium dependent manner (Lessmann and Brigadski T., 2009), which is demonstrated to be mediated by the excitatory neurotransmitters glutamate and acetylcholine (Finsterwald et al., 2010;Navakkode and Korte, 2011).
The nature and the duration of the synaptic modifications that occur as a result from neuronal activity is dependent on several factors. The innervating neuron must stimulate the target neuron sufficiently in order to induce the synthesis and secretion of NTFs (Thoenen, 1995). Also, the persistency of the synaptic modifications in the hippocampus is found to be critically dependent on delayed protein synthesis, which is instantiated as a result of the cytoplasmic calcium influx (Bekinschtein, 2007).
Enrichment of the physical environment
A physically enriched environment has been shown to increase neurogenesis in the hippocampus (Beauquis et al., 2010;Kempermann et al., 1997b), progenitor cell proliferation in the amygdala (Okuda et al., 2009), the expression of BDNF and other NTFs (Kuzumaki et al., 2011;Sun et al., 2010;van et al., 2000;Zhao et al., 2001), and the expession of a number of other genes involved in neuronal structure, synaptic signaling, and plasticity (Rampon et al., 2000).
Interestingly, animal experiments have shown that the detrimental effects of perinatal stress on both the HPA-axis and behavioral responses to stress can be completely reversed by exposure to environmental enrichment (Cui et al., 2006;Francis et al., 2002;Yang et al., 2006). These positive effects of environmental enrichment on brain plasticity and brain functions results have also been found for adult animals who experienced chronic stress (Veena et al., 2009) and in animals with brain injury (Sun et al., 2010;Xu et al., 2009a). Also, an enriched environment is shown to restores normal behavior in animal models of depression (Sifonios et al., 2009).
Fischer et al (2007) demonstrated that an enriched environment recovered learning and memory, correlated with increased histone acetylation (Fischer et al., 2007). This indicates that the functional alterations in response to the enriched environment underlie epigenetic changes. The influence of enriched environments is however not yet demonstrated in human experiments. Nevertheless, these findings suggest an important role for the environment in compensating the detrimental influences of stress on brain structure and function.
Enrichment of the social environment
Many studies, both in rodents and in higher primates including humans, show that at an early age BDNF expression is especially strongly modulated by the amount of social interactions between the youngster and its mother and between the youngster and its peers, and that these interactions can induce long lasting epigenetic changes (See for detailed review: (Branchi, 2009)). Young mice which grow up in a socially enriched environment show in adult life higher BDNF levels in the hippocampus and the hypothalamus, and prolonged survival of newly generated cells in the hippocampus (Branchi et al., 2006). These elevated BDNF levels have in turn been correlated with increased tendencies to engage in social interactions in adult life (Branchi et al., 2006;Branchi, 2009) and an increased resilience to depression ((Calabrese et al., 2009;Curley et al., 2009;D'Andrea et al., 2010).
In contrast, as is discussed in detail in chapter four, isolation from the mother in early life, or receiving less care from the mother reduces BDNF levels and is associated with increased anxiety and stress responsiveness in adults (Calabrese et al., 2009). Humans experiments have reported widely that children who have experienced an aversive social environment were found to be at increased risk for the development of mental health problems in adult life (Calabrese et al., 2009;DE Bellis et al., 2009;Grassi-Oliveira, 2008;Heim et al., 2002;Heim et al., 2008;Heim and Nemeroff, 2001;Parker et al., 2000)
Physical exercise
In the last decades, various beneficial effects of exercise on brain structure and function have been reported. Exercise enhances memory and cognitive functions (Hillman et al., 2008) and is demonstrated to facilitate recovery from brain injury (Devine and Zafonte, 2009). There is some evidence that exercise can decrease the mental decline associated with aging (Plassman et al., 2010) and can reduce symptoms of depression (Gill et al., 2010).
Multiple studies show increased levels of BDNF and other growth factors in the brain in response to physical exercise (Cotman and Berchtold, 2002). A recent study by Gomez-Pinilla et al (2011) demonstrated that the increase of BDNF through exercise, is accomplished by epigenetic alterations, including DNA demethylation in BDNF promoter IV and acetylation of histone H3 (Gomez-Pinilla et al., 2011). Other studies confirmed that exercise promotes BDNF-dependent neuronal plasticity through epigenetic mechanisms. These studies show that exercise inhibits histone deactelyation of the BDNF gene (McGee & Hargreaves, 2004; Avila et al., 2007).
How exercise increases BDNF in the CNS might be explained by the physiological effects of aerobic exercise. Increased BDNF expression in the CNS has been found in aerobic exercise, but not in strength exercise (Goekint et al., 2010;Schiffer et al., 2009). It is suggested that this could be due to the effects of radical oxygen species (ROS) on BDNF expression in the brain (Radak et al., 2008). ROS increases BDNF expression through increasing intracellular calcium influx, which instantiates protein cascades involved in cell survival (Wang, 2006). It is proposed that this is a protective response to ROS-exposure, to maintain homeostasis and prevent the CNS from ROS-induced damage (Radak et al., 2008).
Dietary factors
Both animal and human studies have demonstrated that dietary factors influence cognition and mood, stimulate stimulates neurotrophin expression and enhances neurogenesis in the hippocampus (Fontn-Lozano et al., 2008;Lee et al., 2000;Lee et al., 2002b;Lee et al., 2002a;Mattson et al., 2003). These dietary factors include the magnitude of energy intake as well as the nutritional content of the meal (Fontn-Lozano et al., 2008;Mattson et al., 2003). A study by Huimaraes showed that caloric restriction in patients with schizophrenia increase BDNF values (Guimaraes et al., 2008), which indicates a possible therapeutic implication for caloric restriction.
Apart from energy intake, multiple nutrients have been found to influence BDNF expression significantly. These include, but are not limited to: poly-unsaturated omega-3 fatty acids (Bousquet et al., 2009;Wu et al., 2004), flavonoids (Hou et al., 2010;Williams et al., 2008), zinc (Tsai, 2007) and curcumin (Wang et al., 2010;Xu et al., 2007). Many of these factors have a demonstrated effect on improving cognition (Morley and Banks, 2010;Spencer et al., 2009;Williams et al., 2008), recuding symptoms of depression (Hou et al., 2010;Martins, 2009;Szewczyk et al., 2008) and counteracting the detrimental effects of chronic stress (Xu et al., 2007;Xu et al., 2009b) and brain injury (Mills et al., 2011;Wu et al., 2006).
Sleep
Many studies indicate that sleep plays an important role in learning and memory formation (Graves et al., 2001), probably by replay of the associated neuronal activity and reactivation of neuronal plasticity (Walker and Stickgold, 2006). In turn, there are studies that indicate that sleep loss can have detrimental effects on hippocampal-dependent learning and memory formation (Ruskin et al., 2004). This effect is mediated independently of adrenal stress hormones (Mueller et al., 2008). An animal experiment performed by Hairston et al (2005) demonstrated that the detrimental effects of sleep deprivation are caused by suppression of hippocampal neurogenesis (Hairston et al., 2005).
Although there is currently no direct evidence that sleep deprivation supress's neurogenesis in the adult human brain, there many indications that suggest this might be the case. Imaging studies in humans have demonstrated clearly that sleep plays an important role in optimal functioning of the hippocampus and memory formation (Marshall and Born, 2007;Orban et al., 2006;Peigneux et al., 2004). And although it provides no causal evidence, studies show that patients with chronic insomnia have a significant reduction in hippocampal volume (Riemann et al., 2007), and display disturbances in cognitive functioning (Backhaus et al., 2006;Nissen et al., 2006).
Interestingly, the link between sleep disturbances and depression is well established. Both animal studies and human studies indicate that chronic disturbance of sleep sensitizes the development of mood disorders (Meerlo et al., 2008). In support of this view, an animal study of Guzman-Marin et al (2006) showed that the decreased hippocampal functioning due to sleep deprivation is mediated by a decreased gene expression of BDNF (Guzman-Marin et al., 2006). Taking these findings together, it strongly suggests that via suppression of hippocampal neuronal plasticity, sleep deprivation might decrease hippocampal functioning, and sensitize the individual to the development of a psychiatric disorder.
However, in contrast to one's expectations with regard to these findings, there are multiple studies demonstrating that sleep deprivation causes an acute upregulation of a variety of genes involved in neuronal plasticity, including BDNF (Cirelli, 2002). This seems at first sight to contradict the previously discussed findings. However, the studies discussed by Cirelli et al (2002) that show upregulation of a diverse array of genes involved in neuronal plasticity in response to sleep deprivation, use transient, short periods of sleep deprivation (Cirelli, 2002). This stands in contrast with the previous studies that examine the effects of severe and chronic sleep deprivation on the brain. The response of the brain in terms of changes in gene expression after long periods of sleep deprivation is different from that of short-term sleep deprivation or spontaneous wakefulness (Cirelli, 2002). The beneficial effects of short amounts of sleep deprivation on neuronal plasticity are furthermore illustrated by a study done by Gorgulu et al (2009). This study shows that the positve treatment outcomes of anti-depressive treatment is accelerated when supplemented with short periods of sleep deprivation, with increased serum BDNF levels (Gorgulu and Caliyurt, 2009).
Also, sleep deprivation is demonstrated to acutetely reduce depressive symptoms (Hemmeter et al., 2010). This could be due to the fact that sleep deprivation is found to increases the release of thyroid and estrogen hormones (Baumgartner et al., 1993), which in turn have been related to an enhancement of dopamin release in the prefrontal cortex (Wu et al., 2001). Sleep deprivation also causes an acute elevation of serotonergic turnover in the hypothalamus and increased prolactin levels (Machado et al., 2008).
