Neuronal plasticity and antidepressant action

Antidepressant treatments enhance plasticity and increase neurogenesis in the adult brain, but it has been unclear how these effects influence mood. We propose that like environmental enrichment and exercise, antidepressant treatments enhance adaptability by increasing structural variability within the nervous system at many levels, from proliferating precursors to immature synaptic contacts. Conversely, sensory deprivation and chronic stress reduce this structural variability. Activity-dependent competition within the moodrelated circuits, guided by rehabilitation, then selects for the survival and stabilization of those structures that best represent the internal or external milieu. Increased variability together with competition-mediated selection facilitates normal function, such as pattern separation within the dentate gyrus and other mood-related circuits, thereby enhancing adaptability towards novel experiences. Neuronal plasticity: growth and change The extrinsic and intrinsic milieu becomes represented in the structure and function of neuronal networks during development through neuronal plasticity. In adulthood, this representation is continuously optimized and modulated through plasticity and learning [1]. Plasticity occurs at several levels, from neurogenesis to the adjustment of synaptic weights, and modulates both the structure and function of neuronal networks (Figure 1). Changes in function of the nervous system are essentially always based on a structural change at some level (neuronal, synaptic, protein, or genomic structure), and it is therefore difficult to make clear distinctions between functional and structural plasticity. Plasticity can be conceptualized as two distinct processes. First, structural variability is generated through the overproduction of immature neuronal structures, which occurs at many levels from newborn neurons to the outgrowth of filopodia (Figure 1). Second, selective stabilization among the overproduced structures retains those that best represent the internal or external milieu [2]. Structural variability may be stochastic, although it may also be genetically tuned, but selection is an active process driven by neuronal activity that reflects both extrinsic and intrinsic stimuli. Activity-dependent selection guides the stabilization of functionally relevant neurons and connections by utilizing genes involved in survival and synaptogenesis, or it eliminates weakly or incoherently active structures through the use of genes that underlie apoptosis and pruning [1,3]. The elimination of weakly active neurons and connections is critical for optimizing the signal-tonoise ratio in neuronal networks. Neuronal plasticity can be compared to auditions for a Broadway show: if many candidates audition, the production team can select an optimal performer for each role (and send those not suitable back home), but if only a few people show up, almost all have to be utilized regardless of their talent. During the past few years, neuronal plasticity, and in particular adult neurogenesis, has been implicated in the beneficial effects of antidepressant drugs and electroconvulsive shock treatment (ECS) [4-6][7]. However, it has remained unclear how plasticity and neurogenesis impact mood and anxiety-related behaviors. Here, we provide a framework for how chronic antidepressant drug treatment and ECS might utilize neurogenesis and other forms of neuronal plasticity to influence mood. We argue that antidepressants, environmental enrichment, and exercise increase structural variability at various levels in the nervous system, thereby offering more substrates for the selection process (Figure 1) [7]. Conversely, sensory deprivation and chronic stress would reduce variability and impair adaptability. Whereas acute stress may promote variability and adaptation, chronic stress is considered maladaptive and is associated with a loss of neurons and synapses [8,9]. Furthermore, stress may increase activity in certain brain Castrén E and Hen R (2013). Trends Neurosci. 36(5):259-267. 2/13 regions, such as the amygdala and the mesolimbic dopaminergic system, leading to hypertrophy of these structures. We argue that chronic antidepressant treatments and ECS act at least in part by utilizing a similar mechanism to increase adaptability and facilitate structural and functional reorganization in neuronal networks that have evolved to boost the effects of environmental enrichment, although the cellular and molecular mechanisms may be different. We further suggest that the effects of enrichment and antidepressant treatments that increase plasticity take place at many levels within neuronal networks (Figure 1). Because experience-guided selection constantly eliminates inactive structures, an increase or decrease in variability does not need to influence the mean number of these structures in brain (like counting the number of actors of the final cast does not tell you how many have auditioned), which makes detecting such a change in variability difficult. Therefore, it is currently unclear whether the effects of antidepressants are confined to particular brain areas or whether they occur more ubiquitously throughout the brain. Nevertheless, tougher competition between variable structures increases adaptability towards changes in the external or internal milieu, analogous to the way increased genetic variability contributes to the survival of a species facing a changing environment in the context of evolution. Neurogenesis in the dentate gyrus Adult neurogenesis is an exceptional form of plasticity in which entire neurons are generated and selected for survival in only a very few regions of adult mammalian brain [10]. The two main areas where neurogenesis occurs are the subventricular zone that lines the ventricles and gives rise to neuronal precursors that migrate toward the olfactory bulb, and the subgranular zone that lines the dentate gyrus (DG) of the hippocampus and gives rise to DG granule cells (Figure 2) [10]. Neurogenesis is a plastic process that is regulated by environmental factors. In the hippocampus, various stages of neurogenesis are stimulated by enriched environments, exercise, learning, and antidepressant drugs, and they are inhibited by chronic stress and aging [5,6,11]. Enrichment, antidepressants, and ECS stimulate the proliferation of neural stem cells, their differentiation into neurons, and the survival of the resulting young neurons (Figure 2) [4,12]. Conversely, both acute and chronic stress decrease proliferation and the survival of the newborn neurons in several species, including nonhuman primates [13,14], although increased neurogenesis has not been confirmed in all stress studies [13,14]. Newborn neurons have also been implicated in the adaptation to stress by buffering against it [16]. Furthermore, sensory deprivation decreases proliferation, the choice of a neuronal fate, and the survival of the young neurons [15]. These observations raise the possibility that changes in neurogenesis allow for a better adaptation to a changing environment either instructively by encouraging adaptive behavior [17] or permissively by increasing variability that is then utilized in experience-dependent selection. However, it is also possible that changes in neurogenesis are merely a consequence of these environmental changes. By reviewing the proposed functions of adult-born neurons, we can attempt to resolve these options. Neurogenesis, pattern separation, and generalization Recent functional studies of adult-born dentate granule neurons have focused on their potential role in pattern separation because increasing evidence from electrophysiological studies indicates that the DG is involved in pattern separation [18]. It has been proposed that pattern separation enables the processing of similar experiences as distinct memories and is critical for memory formation, although direct evidence for this mechanism is still missing. For example, pattern separation may enable us to remember two distinct beach vacations or where we last parked our car even though the parking garage and general context may be the same each morning. In a number of rodent models, both loss and gain of function studies show that increases in neurogenesis improve, and decreases in neurogenesis impair, pattern separation [19,20]. Furthermore, some evidence exists indicating that young neurons are involved in discriminating between complex odor mixtures in the olfactory bulb, which may involve a process similar to pattern separation [21]. Pattern separation appears to be impaired both during normal aging and in individuals with Mild Cognitive Impairment [22]. In addition, functional imaging studies have identified abnormal activity Castrén E and Hen R (2013). Trends Neurosci. 36(5):259-267. 3/13 in the dentate gyrus and CA3 of individuals with age related memory impairments when they perform a pattern separation task [23]. In the psychiatric literature, the term pattern separation is rarely used because it refers to a cognitive process that is usually not tested in psychiatric patients. However, generalization is a phenotype that is often associated with anxiety and mood disorders [24]. Generalization can be defined as our tendency to lump together similar experiences particularly when they have a strong emotional content. For example the sight of a plane flying over a skyscraper may remind us of 9/11. Generalization may therefore be considered the opposite of pattern separation. Generalization is a double-edged sword: in small doses it is clearly protective to avoid similar dangerous situations, for example, if you were hit by a car when you crossed a dangerous intersection a little generalization will enable you to be careful each time you cross this intersection; however, too much generalization may result in the fear to cross any street, which would clearly be maladaptive. Like pattern separation, generalization may be c