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Stress, Dopamine, and Puberty
Stress, Dopamine, and Puberty 529
Stress, Dopamine, and Puberty S L Andersen and M P Leussis, McLean Hospital, Belmont, MA, USA ã 2009 Elsevier Ltd. All rights reserved.
Stress, Puberty, and Adolescence A stressor is anything that is perceived by the individual to cause emotional, mental, or physical strain. This definition suggests that awareness of the stress is vital for its impact on both emotional and cognitive processing. Thus, what is considered stressful needs to be placed in developmental context when it is applied to immature systems. For example, conflict and missed deadlines are stressors for adolescents and adults, whereas neglectful parents or no friends are stressors for children. Relevant examples for adult animals in a species-specific context include choice conflicts or delay of reinforcement paradigms, whereas maternal deprivation or social isolation model childhood and young adolescent stressors. Ageappropriate stressors are important for correct interpretation of behavioral and neurochemical responses at different stages of development. Development occurs in a series of phases, defined physiologically or socially. The term puberty refers to the achievement of reproductive fitness hailed by secondary sex characteristics and maturity of the reproductive systems. As part of this process, adolescence describes the period between the onset of puberty and adulthood when the individual defines and refines the sense of self in terms of social values, personal values, and future goals. The use of the terms puberty versus adolescence in this article will reflect whether the topic refers to physiological or social changes and the timing of the developmental period discussed. For example, stress during adolescence may depend more on social context than physiological deprivation given the importance of social development during this period. Adolescence will also be used to refer to the period of development that spans between puberty onset and adulthood. As outlined in this article, understanding how the dopamine system develops during the transitions between childhood, adolescence, and adulthood sets the stage for framing the uniqueness of the impact of stress on behavior, neurochemistry, and neuroanatomy.
The Dopamine System Neuroanatomy
The catecholaminergic dopamine system is more localized in its innervation patterns relative to many other neurotransmitter systems. Dopaminergic cell bodies, also known as A9 and A10, emanate from the ventral tegmental nucleus (VTA) and the substantia nigra, respectively. Smaller, less well-characterized dopamine terminals have been identified in the amygdala, hippocampus, and cerebellum. From the VTA, separate dopaminergic neurons project to either the nucleus accumbens and comprise the mesolimbic dopamine system, or the prefrontal cortex and comprise the mesocortical system. The substantia nigra sends projections to the caudate and putamen (collectively referred to as the striatum), and forms the nigrostriatal dopamine system. Signaling Mechanisms in the Dopamine System
The signaling mechanisms of the dopamine system are associated with five main receptor subtypes, referred to as D1–D5 (Figure 1). The majority of these receptors are G-protein-coupled receptors (GCPRs). D1 and D5 are more excitatory in nature, are linked to stimulatory G-proteins, and classically increase the activity of the second messenger cyclic adenosine monophosphate (cAMP). In contrast, D2–D4 dopamine receptors are inhibitory in nature, couple with inhibitory G-proteins, and reduce cAMP activity. This is merely the beginning of the signaling cascade, as other second messengers (protein kinases) and the inositol triphosphate (IP3) system are also involved. Dopamine receptor signaling mechanisms, activated by environmental changes, can induce transcriptional regulating proteins, which ultimately leads to changes in gene transcription. Enhanced expression of cyclic AMP response element-binding protein (CREB) and delta-Fos subunit B (DFosB), have been extensively studied. It is believed that changes in these proteins signal the beginning of long-term alterations, or plasticity, that occur in response to drugs of addiction or stress. Changes in immediate early gene expression, notably the Fos and Jun genes, are among the most commonly reported. Their expression, in turn, increases the production of numerous proteins that produce the enduring actions of
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Figure 1 Dopamine receptor signaling cascades. Dopamine acts at G-protein-coupled receptors to produce activational (via D1/D5 receptors) or inhibitory effects (via the D2 family (D2–D4)) overall. Dopamine acting at D1/D5 receptors predominantly activates the stimulatory G-protein-coupled receptors (Gs), which upregulate adenylyl cyclase activity, leading to an increase in cAMP. Higher levels of cAMP activate protein kinase A, which phosphorylates many proteins, including transcriptional activators, and membrane-bound ion pumps and channels. Phosphorylation of ion pumps/channels produce short-term alterations in the membrane potential, causing the cell to become more or less likely to fire. In contrast, longer-term effects are seen through the phosphorylation of transcription factors such as CREB and DFosB. These transcription factors ultimately increase the production of proteins, including c-fos, neurotrophins, and neuropeptides. Dopamine at D2–D4 receptors activates the inhibitory G-protein-coupled receptors (Gi), which decreases adenylyl cyclase activity. Dopamine can also act through a secondary D1/D5 pathway, via Gq receptors and the phosphatidylinositol pathway. In this pathway, dopamine binding increases phospholipase C activity, which produces inositol triphosphate and diacylglycerol from phosphatidylinositol. Increased levels of diacylglycerol activate protein kinase C, which phosphorylates other kinases such as mitogenactivated protein kinase, and transcription factors such as CREB. Higher levels of inositol triphosphate increase cytoplasmic Ca2þ levels, thereby activating calcium-dependent kinases, which further continue the process of protein phosphorylation and activation. AC, adenylyl cyclase; AGS3, activator of G-protein signaling 3; BDNF, brain-derived neurotrophic factor; cAMP, cyclic adenosine monophosphate; CREB, cAMP response element-binding protein; DA, dopamine; DAG, diacylglycerol; DFosB, delta-Fos subunit B; GTP, guanosine triphosphate; IEGs, immediate early genes; IP3, inositol triphosphate; MAPK, mitogen-activated protein kinase; PIP2, phosphatidylinositol; PLC, phospholipase C; TCF, transcription factor.
dopamine receptor activation. Most of this work has been performed in animals exposed to drugs of addiction. However, because stress and addictive agents often work by the same mechanistic cascades, the information from stimulant studies is likely to transfer to stress exposure. This represents an area that is tremendously understudied to date.
Brain Development and the Dopamine System Overproduction and Elimination of Synapses during Puberty
Profound brain changes occur during the course of postnatal development and adolescence and represent
the final phase of this transition. Cortical structures, including the prefrontal cortex, and subcortical structures, including the striatum and nucleus accumbens, undergo an exuberant overproduction of synapses and associated signaling molecules between childhood and adolescence. This is subsequently followed by the selective elimination, or pruning, of synapses before adulthood. This pruning is similar to what occurs with trees: branches (dendrites) are selectively cut back to optimize growth potential (or in the case of the brain, efficiency) to match the needs of the environment. In humans, cortical gray matter volume reaches peak density at 11.6 years in females and 12.2 years in males. In rats, similar changes in density are observed at approximately 40 days of age. For all mammalian species, the timing of these synaptic
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density changes coincides with the onset of puberty. However, it is noteworthy that different brain regions have their own unique course of development. For example, the striatum reaches peak dopamine receptor density at pubertal onset, and prunes shortly thereafter. The later-developing prefrontal cortex attains maximum receptor density at the same age, but delays pruning until young adulthood. This differential time course has been used to explain why motor disorders (attention-deficit/hyperactivity disorder and Tourette’s syndrome) affect children, whereas schizophrenia typically emerges during young adulthood. Different periods of vulnerability are associated with the individual trajectory of a given brain region. Thus, in order to understand the impact of stress exposure during development, it is imperative to appreciate the state of maturity of the underlying trajectory at the time of insult. Functional Development of the Dopamine System
Striatum and nucleus accumbens The subcortical structures of the dopamine system, the striatum and the nucleus accumbens, demonstrate functional changes during the onset of puberty. Dopamine D1 and D2 receptors are overproduced in the striatum, but not in the nucleus accumbens. Extracellular levels of dopamine decrease modestly during puberty in these regions. Dopamine autoreceptors regulate the rate of dopamine synthesis and release much like a thermostat functions to control fluctuations in temperature. Despite this regulatory role, the sensitivity of the dopamine autoreceptors does not change during puberty. These data suggest that changes within other systems during puberty mediate the observed functional changes in subcortical dopamine structures. The impact of acute stress on either the striatum or the accumbens is not well understood. The striatum is associated with motor patterns, including stereotypies, habit learning, and initiation of movement. The nucleus accumbens plays vital roles in activity and reward. During pubertal onset, spontaneous locomotor activity reaches its highest point (females are more active than males), and reward systems are vulnerable to the addictive effects of drug exposure. Animal handling prior to testing enhances cocaineinduced locomotion relative to adults, suggesting enhanced reactivity. These behaviors reflect changes within the dopamine system, but are not well characterized as they relate to acute stress per se. The effects of chronic, early life stress on this system are of interest and are discussed below. Prefrontal cortex The functional activity of the prefrontal cortex does not come on-line fully until the
onset of puberty. This increase in dopaminergic activity is important for understanding a number of adolescent transitions. Immunohistochemistry shows that dopaminergic innervation of the prefrontal cortex approaches adult levels during puberty. Along with the increase in innervation, functional rearrangements also occur that increase dopamine activity in response to external stimuli. Dopamine D1 and D2 receptor density peaks during this period before being pruned back in adulthood. Dopamine receptors increase by 38%, plateau during puberty, and are ultimately pruned 33% in adulthood in the rat. Cyclic AMP levels are 35% higher during adolescence than adulthood. This enhancement of dopamine function during puberty may be partly related to the simultaneous loss of regulatory processes. Although poorly understood, modulation of dopamine synthesis in the prefrontal cortex wanes during pubertal onset and is absent by adulthood. Taken together, the cortical dopamine system rapidly reaches an adultlike state during this time. Circuitry within these regions becomes increasingly complex, as innervation from the dopaminergic cell bodies and other neurotransmitter systems continues during puberty. Connections between stress-related brain regions also become more adultlike during puberty. Once the perception of stress has occurred, activational systems, such as glutamatergic efferents to various emotional and cognitive brain regions, are responsible for the course of action. Sex Differences in the Dopamine System during Puberty
Sex differences exist in the immature dopamine system. It is often the case that females overproduce (and prune) less than males. Dopamine receptors are overproduced in the striatum of males during puberty, whereas little change in either D1 or D2 receptor density is observed in females. The pruning of D1 and D2 receptors shows that density changes by 54% and 63%, respectively, in the striatum, and approximately 25% in the accumbens of males between 40 and 80 days of age. This is not to imply that females do not significantly reorganize during adolescence. For instance, signaling mechanisms, including cAMP, in females are elevated during this period before pruning in adulthood. In preparation for reaching sexual maturity, levels of the gonadal hormones estrogen and testosterone rise in the prepubescent subject. However, their dramatic rise seems to have little impact on the neuroanatomy of the dopamine system. Given the profound sex differences that exist in the dopamine system, it is plausible to hypothesize that testosterone increases the overproduction of dopamine receptors or that
532 Stress, Dopamine, and Puberty
estrogen suppresses it. Neither seems to be the case. Estrogen in adults or cell cultures increases dendritic branching, yet neuroanatomical changes in female adolescents are not observed. Based on immunohistochemistry with tyrosine hydroxylase antibodies (a marker that stains the rate-limiting enzyme in dopamine production), dopaminergic innervation of the three major terminal fields does not change with age in females. In addition, removal of the gonadal hormones well before they surge does not alter dopamine expression. These data suggest that gonadal hormones are not involved in the activational phases of changes within the dopamine system. Rather, sex differences may be organized during the prenatal period.
Stress Reactivity during Puberty The Hypothalamic–Pituitary–Adrenal Axis and Stress Response
In order to understand stress reactivity, it is necessary to step back and briefly discuss the maturation of the hormonal system of stress responses. The hypothalamic–pituitary–adrenal (HPA) axis is involved in the secretion of stress hormones. Activation of the paraventricular nucleus of the hypothalamus (PVN) is involved in the release of corticotropin-releasing hormone (CRH), which activates the cascade of stress-related changes at the hormonal level. The PVN receives dopaminergic innervation, and thus is modulated by higher-level processing of stressors. CRH travels to the pituitary, causing the release of adrenocorticotropin hormone, which ultimately signals the release of the stress effector hormone cortisol (human and nonhuman primates) and corticosterone (rodents) from the adrenal glands. Cort (abbreviated as such to capture both hormone versions) then travels back to the brain to signal stressrelated changes. The onset of puberty is a transition point in HPA reactivity. Cort activation following acute restraint stress is more pronounced and prolonged in adolescent than in adult rats. Adolescent rats secrete more Cort in response to acute restraint stress than adult rats. Moreover, the response is larger in female than male adolescent rats. The Cort response following chronic stress, however, differs between adolescents and adults. Adolescent rats with a history of chronic stress exposure return to baseline levels faster than adults. Age differences in stress-related reactivity are observable with c-fos immunoreactivity in the PVN. c-fos is often used as a marker of neuronal activity and can be used to map where changes occur. Prepubertal male rats have increased c-fos immunoreactivity
in CRH-containing neurons of the PVN relative to adults in response to an acute stressor. These findings suggest that the prepubertal rat is more sensitive to the effects of stressful events than adults. They also raise the issue of what is initiating this cascade of stressrelated effects.
Dopamine Systems and Stress Responsiveness Of the three primary ascending dopamine systems, the mesocortical dopamine system is the one commonly associated with stress responses. The prefrontal cortex has an abundant amount of glucocorticoid receptors, second only to the hippocampus, which makes the prefrontal cortex particularly vulnerable to stress and its cascade of effects. In adults, stressors including footshock, restraint, and hotplate preferentially increase dopamine release in the prefrontal cortex. The nucleus accumbens is also activated by these stressors, but to a lesser extent than the prefrontal cortex. The striatum is minimally activated in response to acute stressors, but may be more involved in long-term compensations involving habits. Stress Reactivity in the Dopamine System Emerges with Age
It is during pubertal onset that the cortex becomes increasingly vulnerable to the acute effects of stress relative to younger and older ages. Evidence from a pharmacological stressor, the GABAergic antagonist FG-7142, demonstrates that neuronal activity within the three major dopamine systems shifts in dominance. In this study, changes in the immediate early gene c-fos were quantified following FG-7142 and converted to a percentage of total c-fos immunolabeled neurons to derive an index of maturation. The subcortical structures are significantly activated before puberty and may be more vulnerable to stress at this age. These younger animals do not show the adult-typical pattern of dominant prefrontal cortex activation. Not surprisingly, the adult-typical pattern matures between 18 and 45 days of age in the rat – coincident with the onset of puberty. Further, c-fos immunolabeling is enhanced in the prefrontal cortex at 45 days of age relative to adult rats, demonstrating that an acute stressor during adolescence has a greater impact on cortical structures than comparable exposure in adulthood. These findings offer a neurochemical explanation for why children are more likely to increase their activity levels in response to stress. In contrast, as cortically based stress reactivity emerges, adolescents and adults experience stress on a more cognitive basis.
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depressive-like behaviors in rats. This test was designed to parse controllable from uncontrollable stress effects, and relies on cortical modulation. Normal, pubertal female rats demonstrate a higher level of helplessness following one day of conditioning to a series of escalating tail shocks. This sex difference was reversed, however, following a 5-day social stressor that occurs immediately before the onset of puberty. After this subchronic stress exposure, males demonstrate increased learned helplessness, whereas females show some degree of improvement in this behavior.
Circuits Involving Dopaminergic Modulation of Stress
Prefrontal cortex The functional nature of the prefrontal cortex places it in a vulnerable niche. The cortex is involved in motivation and cognition, in part by integrating environmental and emotional information and deciding the next course of action. As an example, abnormality or immaturity of the system is associated with impulsive or inappropriate decisions for a given context. The cortex, however, does not act alone. Connections to other brain regions play a critical role in stress responses during puberty. One such circuit loop is the prefrontal cortex to dorsal raphe. Here, the prefrontal cortex has the important role of differentiating controllable from uncontrollable stress (Figure 2). The learned helplessness paradigm models
The amygdala also plays an important role in stress responses, but more at the level of mediating fear responses. Fear, by definition, is a reaction to a future,
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Figure 2 Learned helplessness paradigm. The learned helplessness model of depression is based on the differential response of rats to (a) controllable shock, (b) uncontrollable shock, or (c) no shock. Controllable (escapable) shock rats can terminate the tail shock by completing a behavioral response (turning a wheel). Uncontrollable (inescapable) shock rats are yoked to the controllable shock rat, so they receive the same number and duration of shocks, but are unable to control the termination of each shock. No shock rats are restrained similarly to the other two rats, but receive no shock during the training phase. The latency to escape a footshock (out of 30 s) and the number of escape failures (out of 30 trials) are recorded in a shuttlebox the next day. Leaned helplessness is defined as longer latencies to escape (f) and a greater number of escape failures than the controllable shock animals (A) or no shock controls (C). The anatomical circuit involved in dissociating controllable from uncontrollable stress involves the prefrontal cortex (PFC) and dorsal raphe nucleus (DRN). (d) Following controllable stress, glutamatergic projections from the PFC act on GABAergic interneurons in the DRN to suppress activation of serotonergic neurons. (e) Following uncontrollable stress, there is an increase in activation of serotonergic (5-HT) DRN neurons that project to the PFC, which serves in part to inhibit the glutamatergic neurons projecting back to the DRN. In the case of either controllable or uncontrollable stress, dopamine (DA) from the ventral tegmental nucleus (VTA) serves to signal the presence of a stressor. This figure and description is based on the seminal work of Maier and colleagues: Amat J, Baratta MV, Paul E, Bland ST, Watkins LR, and Maier SF (2005) Medial prefrontal cortex determines how stressor controllability affects behavior and dorsal raphe nucleus. Nature Neuroscience 8: 365–371.
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probabilistic event based on past, conditioned responses. As such, fear responses are highly dependent on the context. Dopamine, via innervation from the VTA, plays an important role in the plasticity that underlies the associations between the context and the unconditioned, fear-eliciting stimulus. Increases in cortical dopamine are correlated with increased anxiety that increases during puberty. How levels or innervation of the amygdalar dopamine system change in response to stress during puberty is not known and remains another area of future investigation. More is known, however, on the innervation of fibers from the amygdala to the prefrontal cortex. The prefrontal cortex receives input from the amygdala to integrate environmental contextual information with emotional processing. This innervation occurs throughout postnatal brain development, but begins to plateau during the onset of puberty. Studies with systemic and microinjections of dopamine agonists, in addition to dopamine depletions, show that these effects are modulated by dopamine. Again, the developmental profile of this effect is not known. Synthesis
Taken together, data from Cort changes, c-fos localization, and behavioral paradigms suggest that the responses to stressful events rapidly shift during puberty onset. Increased dopaminergic activity in the prefrontal cortex is likely to play a significant role in the processing of environmental events, and thus facilitate enhanced responsiveness to stressful events. Acute stress during puberty onset has a greater impact on females compared with males. However, chronic stress exposure immediately before testing changes this relationship. Males have increased responsiveness within the HPA axis and in learned helplessness following chronic stress exposure when challenged during the pubertal period. The effect on adolescents is short lived, and animals show a return to baseline faster than adult cohorts. Studies such as these further suggest that the stress system is programmed by previous experiences differently during development when compared with adults.
Programming of Immature Stress-Responsive Systems Sensitive Periods of Development
As discussed above, the brain develops in a series of stages. Overproduction and pruning of synaptic connections and signaling mechanisms program the brain to match the demands of the environment. What this means is that stress responses are appropriate for the
level of stress that one has experienced. The immature brain, in turn, encodes these demands by pruning appropriately. However, the timing of stress experiences significantly influences which brain areas are vulnerable. Brain areas undergoing the most change are likely to be affected by stress exposure to a greater degree than those that have yet to overproduce connections or have already pruned. These periods of selective vulnerability are known as sensitive periods. The impact of stressful events on the immature brain will depend on the sensitive period during which the stressor occurred. Early Postnatal Stressors and Brain Development
In order for something to be perceived as stressful, it has to involve the manipulation of something that is highly relevant to the organism. During early postnatal life, one of the single most important variables is the level of parental (predominantly maternal) care. Therefore, it should not be surprising that manipulation of the level of maternal care significantly affects the maturation of stress-related systems. All mammalian species studied to date that have significant variations in maternal care experience changes in Cort responses later in life, although exceptions occur for individual differences. Events set in motion early in life program the formation of brain anatomy and functional impact follows suit. While detailed timecourses of functional changes within the dopamine system have not been assessed during puberty, it is likely that the impact of early life events manifests during this period. Rats have been the most-studied species in maternal deprivation paradigms, and the discussion here will be limited to rodent studies. Early maternal deprivation alters the overproduction of synapses that occurs during adolescence. The most vulnerable region affected is the hippocampus, which fails to overproduce synapses between puberty and adulthood in animals that were stressed early in life. Early stress, however, has little impact on the dopamine system in the prefrontal cortex. The nucleus accumbens shell, on the other hand, fails to overproduce dopaminergic terminals between puberty and adulthood in maternally deprived animals. Dopamine D1 receptors are elevated in the accumbens, with no observable change in the striatum during puberty. The rest of the results that are discussed are based on adult outcomes of the deprivation. Maternal deprivation decreases the density of dopamine transporters in the accumbens. This may explain why cocaine-stimulated dopamine release is higher in these animals. To compensate, animals with a history of maternal deprivation will self-administer
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more cocaine relative to controls in adulthood. As the propensity that stimulant abuse in humans emerges during the adolescent period, these changes most likely emerge during this period. Late Postnatal Stressors and Brain Development
The alternative paradigm to early maternal deprivation involves social isolation beginning from the time of weaning (prepubertal) into adulthood. This paradigm produces a number of behavioral changes linked with reduced cortical dopamine that include deficits in sensorimotor gating of the acoustic startle response, increased locomotion in response to novelty, and enhanced dopamine levels in the prefrontal cortex. Since this paradigm spans across puberty into adulthood, it is difficult to speculate as to when this social stressor exerts its effects on the dopamine system.
Clinical Impact of Stress during Puberty The transition between childhood and adolescence is a unique period of vulnerability. It is during this period that adolescents (males more so than females) engage in risky behaviors, novelty-seeking, and peerdirected behavior including the abuse of substances. Postpubertal changes also serve as a permissive factor for the expression of mental illnesses that are associated with stress, including schizophrenia and depression. For example, stressful events during adolescence often precipitate the first psychotic episode, which on average occurs in males an average of 6 years earlier than in females. Traumatic stress also effects adolescent transitions in brain development, especially within the latedeveloping prefrontal cortex. Exposure to stress is associated with an increase or a decrease in the size of this region, if the timing of the exposure is before or after puberty, respectively. In clear-cut cases of significant, traumatizing, stress, males are affected more than females as cognition is often impaired. For females, the onset of puberty brings with it its own unique challenges. As social roles are defined, the emergence of mood disorders affects females 2.3-fold more than males and rises from 3% of the population to an estimated 8% during adolescence. It is possible that stress during puberty affects the amygdala/cortical development in females, which would increase depression and anxiety. Part of the emerging role of the prefrontal cortex during this time is to modulate stress responses. Mentally healthy individuals are able to separate stressors into these two categories of controllable and uncontrollable and deal with them accordingly.
In contrast, individuals with depression, anxiety, and schizophrenia perceive most stressors as uncontrollable and become overwhelmed (Figure 2). These disorders are associated with elevated levels of cortical dopamine activity in response to stress. The parallel timing of the significant rise in dopamine activity and the prevalence of these disorders during puberty is more than just coincidence. Although this has yet to be demonstrated conclusively, it is likely that increased cortical dopamine plays a role in the perceptual ‘switch’ between controllable versus uncontrollable stress. On the other hand, the pubertal transition, dopamine, and its relationship to stress provide a window of opportunity for some. The waning of motor tics in Tourette’s syndrome during puberty reflects the benefit of positive changes associated with enhanced dopamine activity in the cortex. Generally, tics are exacerbated in response to stress in Tourette’s syndrome patients. The prevalence of tics (or their willful modulation) improves during adolescence.
Conclusions Despite the universal nature of the stressful transitions that are associated with the onset of puberty, relatively little research has been conducted on this important topic. The emerging role of cortical dopamine increases the perception of stress during puberty. Whether this translates into more or less controllability over life’s strife and stress most likely depends on genetic and stress history. What is becoming increasingly clearer, however, is that events that happen before this transition can drastically shape the ability to deal with stressful events later on. The occasion to intervene during this potential window of opportunity beckons more researchers to explore what this area may offer. See also: Stress and Cognition; Stress and Suicide; Stress and Vulnerability to Brain Damage; Stress Response: Sex Differences; Stress Response and Self-Esteem; Stress, Sex and Adolescent Nicotine Response; Stress, Cytokines and Depressive Illness; Stress, the HPA Axis and Depressive Illness; Stress: Definition and History; Stress: Homeostasis, Rheostasis, Allostasis and Allostatic Load.
Further Reading Amat J, Baratta MV, Paul E, Bland ST, Watkins LR, and Maier SF (2005) Medial prefrontal cortex determines how stressor controllability affects behavior and dorsal raphe nucleus. Nature Neuroscience 8: 365–371.
536 Stress, Dopamine, and Puberty Andersen SL (2002) Changes in the second messenger cyclic AMP during development may underlie motoric symptoms in attention deficit/hyperactivity disorder (ADHD). Behavioral Brain Research 130: 197–201. Andersen SL (2003) Trajectories of brain development: Point of vulnerability or window of opportunity? Neuroscience and Biobehavioral Reviews 27: 3–18. Andersen SL and Teicher MH (2004) Delayed effects of early stress on hippocampal development. Neuropsychopharmacology 29: 1988–1993. Kosten TA, Zhang XY, and Kehoe P (2006) Heightened cocaine and food self-administration in female rats with neonatal isolation experience. Neuropsychopharmacology 31: 70–76. Lyss PJ, Andersen SL, LeBlanc CJ, and Teicher MH (1999) Degree of neuronal activation following FG-7142 changes across regions during development. Developmental Brain Research 116: 201–203.
Meaney MJ and Aitken DH (1985) The effects of early postnatal handling on hippocampal glucocorticoid receptor concentrations: Temporal parameters. Brain Research 354: 301–304. Romeo RD, Lee SJ, and McEwen BS (2004) Differential stress reactivity in intact and ovariectomized prepubertal and adult female rats. Neuroendocrinology 80: 387–393. Spear L (2000) The adolescent brain and age-related behavioral manifestations. Neuroscience and Biobehavioral Reviews 24: 417–463. Teicher MH (2002) Scars that won’t heal: The neurobiology of child abuse. Scientific American 286: 68–75. Wommack JC and Delville Y (2002) Chronic social stress during puberty enhances tyrosine hydroxylase immunoreactivity within the limbic system in golden hamsters. Brain Research 933: 139–143. Young EA and Altemus M (2004) Puberty, ovarian steroids, and stress. Annals of the New York Academy of Science 1021: 124–133.
Stress, Dopamine, and Puberty S L Andersen and M P Leussis, McLean Hospital, Belmont, MA, USA ã 2009 Elsevier Ltd. All rights reserved.
Stress, Puberty, and Adolescence A stressor is anything that is perceived by the individual to cause emotional, mental, or physical strain. This definition suggests that awareness of the stress is vital for its impact on both emotional and cognitive processing. Thus, what is considered stressful needs to be placed in developmental context when it is applied to immature systems. For example, conflict and missed deadlines are stressors for adolescents and adults, whereas neglectful parents or no friends are stressors for children. Relevant examples for adult animals in a species-specific context include choice conflicts or delay of reinforcement paradigms, whereas maternal deprivation or social isolation model childhood and young adolescent stressors. Ageappropriate stressors are important for correct interpretation of behavioral and neurochemical responses at different stages of development. Development occurs in a series of phases, defined physiologically or socially. The term puberty refers to the achievement of reproductive fitness hailed by secondary sex characteristics and maturity of the reproductive systems. As part of this process, adolescence describes the period between the onset of puberty and adulthood when the individual defines and refines the sense of self in terms of social values, personal values, and future goals. The use of the terms puberty versus adolescence in this article will reflect whether the topic refers to physiological or social changes and the timing of the developmental period discussed. For example, stress during adolescence may depend more on social context than physiological deprivation given the importance of social development during this period. Adolescence will also be used to refer to the period of development that spans between puberty onset and adulthood. As outlined in this article, understanding how the dopamine system develops during the transitions between childhood, adolescence, and adulthood sets the stage for framing the uniqueness of the impact of stress on behavior, neurochemistry, and neuroanatomy.
The Dopamine System Neuroanatomy
The catecholaminergic dopamine system is more localized in its innervation patterns relative to many other neurotransmitter systems. Dopaminergic cell bodies, also known as A9 and A10, emanate from the ventral tegmental nucleus (VTA) and the substantia nigra, respectively. Smaller, less well-characterized dopamine terminals have been identified in the amygdala, hippocampus, and cerebellum. From the VTA, separate dopaminergic neurons project to either the nucleus accumbens and comprise the mesolimbic dopamine system, or the prefrontal cortex and comprise the mesocortical system. The substantia nigra sends projections to the caudate and putamen (collectively referred to as the striatum), and forms the nigrostriatal dopamine system. Signaling Mechanisms in the Dopamine System
The signaling mechanisms of the dopamine system are associated with five main receptor subtypes, referred to as D1–D5 (Figure 1). The majority of these receptors are G-protein-coupled receptors (GCPRs). D1 and D5 are more excitatory in nature, are linked to stimulatory G-proteins, and classically increase the activity of the second messenger cyclic adenosine monophosphate (cAMP). In contrast, D2–D4 dopamine receptors are inhibitory in nature, couple with inhibitory G-proteins, and reduce cAMP activity. This is merely the beginning of the signaling cascade, as other second messengers (protein kinases) and the inositol triphosphate (IP3) system are also involved. Dopamine receptor signaling mechanisms, activated by environmental changes, can induce transcriptional regulating proteins, which ultimately leads to changes in gene transcription. Enhanced expression of cyclic AMP response element-binding protein (CREB) and delta-Fos subunit B (DFosB), have been extensively studied. It is believed that changes in these proteins signal the beginning of long-term alterations, or plasticity, that occur in response to drugs of addiction or stress. Changes in immediate early gene expression, notably the Fos and Jun genes, are among the most commonly reported. Their expression, in turn, increases the production of numerous proteins that produce the enduring actions of
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Figure 1 Dopamine receptor signaling cascades. Dopamine acts at G-protein-coupled receptors to produce activational (via D1/D5 receptors) or inhibitory effects (via the D2 family (D2–D4)) overall. Dopamine acting at D1/D5 receptors predominantly activates the stimulatory G-protein-coupled receptors (Gs), which upregulate adenylyl cyclase activity, leading to an increase in cAMP. Higher levels of cAMP activate protein kinase A, which phosphorylates many proteins, including transcriptional activators, and membrane-bound ion pumps and channels. Phosphorylation of ion pumps/channels produce short-term alterations in the membrane potential, causing the cell to become more or less likely to fire. In contrast, longer-term effects are seen through the phosphorylation of transcription factors such as CREB and DFosB. These transcription factors ultimately increase the production of proteins, including c-fos, neurotrophins, and neuropeptides. Dopamine at D2–D4 receptors activates the inhibitory G-protein-coupled receptors (Gi), which decreases adenylyl cyclase activity. Dopamine can also act through a secondary D1/D5 pathway, via Gq receptors and the phosphatidylinositol pathway. In this pathway, dopamine binding increases phospholipase C activity, which produces inositol triphosphate and diacylglycerol from phosphatidylinositol. Increased levels of diacylglycerol activate protein kinase C, which phosphorylates other kinases such as mitogenactivated protein kinase, and transcription factors such as CREB. Higher levels of inositol triphosphate increase cytoplasmic Ca2þ levels, thereby activating calcium-dependent kinases, which further continue the process of protein phosphorylation and activation. AC, adenylyl cyclase; AGS3, activator of G-protein signaling 3; BDNF, brain-derived neurotrophic factor; cAMP, cyclic adenosine monophosphate; CREB, cAMP response element-binding protein; DA, dopamine; DAG, diacylglycerol; DFosB, delta-Fos subunit B; GTP, guanosine triphosphate; IEGs, immediate early genes; IP3, inositol triphosphate; MAPK, mitogen-activated protein kinase; PIP2, phosphatidylinositol; PLC, phospholipase C; TCF, transcription factor.
dopamine receptor activation. Most of this work has been performed in animals exposed to drugs of addiction. However, because stress and addictive agents often work by the same mechanistic cascades, the information from stimulant studies is likely to transfer to stress exposure. This represents an area that is tremendously understudied to date.
Brain Development and the Dopamine System Overproduction and Elimination of Synapses during Puberty
Profound brain changes occur during the course of postnatal development and adolescence and represent
the final phase of this transition. Cortical structures, including the prefrontal cortex, and subcortical structures, including the striatum and nucleus accumbens, undergo an exuberant overproduction of synapses and associated signaling molecules between childhood and adolescence. This is subsequently followed by the selective elimination, or pruning, of synapses before adulthood. This pruning is similar to what occurs with trees: branches (dendrites) are selectively cut back to optimize growth potential (or in the case of the brain, efficiency) to match the needs of the environment. In humans, cortical gray matter volume reaches peak density at 11.6 years in females and 12.2 years in males. In rats, similar changes in density are observed at approximately 40 days of age. For all mammalian species, the timing of these synaptic
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density changes coincides with the onset of puberty. However, it is noteworthy that different brain regions have their own unique course of development. For example, the striatum reaches peak dopamine receptor density at pubertal onset, and prunes shortly thereafter. The later-developing prefrontal cortex attains maximum receptor density at the same age, but delays pruning until young adulthood. This differential time course has been used to explain why motor disorders (attention-deficit/hyperactivity disorder and Tourette’s syndrome) affect children, whereas schizophrenia typically emerges during young adulthood. Different periods of vulnerability are associated with the individual trajectory of a given brain region. Thus, in order to understand the impact of stress exposure during development, it is imperative to appreciate the state of maturity of the underlying trajectory at the time of insult. Functional Development of the Dopamine System
Striatum and nucleus accumbens The subcortical structures of the dopamine system, the striatum and the nucleus accumbens, demonstrate functional changes during the onset of puberty. Dopamine D1 and D2 receptors are overproduced in the striatum, but not in the nucleus accumbens. Extracellular levels of dopamine decrease modestly during puberty in these regions. Dopamine autoreceptors regulate the rate of dopamine synthesis and release much like a thermostat functions to control fluctuations in temperature. Despite this regulatory role, the sensitivity of the dopamine autoreceptors does not change during puberty. These data suggest that changes within other systems during puberty mediate the observed functional changes in subcortical dopamine structures. The impact of acute stress on either the striatum or the accumbens is not well understood. The striatum is associated with motor patterns, including stereotypies, habit learning, and initiation of movement. The nucleus accumbens plays vital roles in activity and reward. During pubertal onset, spontaneous locomotor activity reaches its highest point (females are more active than males), and reward systems are vulnerable to the addictive effects of drug exposure. Animal handling prior to testing enhances cocaineinduced locomotion relative to adults, suggesting enhanced reactivity. These behaviors reflect changes within the dopamine system, but are not well characterized as they relate to acute stress per se. The effects of chronic, early life stress on this system are of interest and are discussed below. Prefrontal cortex The functional activity of the prefrontal cortex does not come on-line fully until the
onset of puberty. This increase in dopaminergic activity is important for understanding a number of adolescent transitions. Immunohistochemistry shows that dopaminergic innervation of the prefrontal cortex approaches adult levels during puberty. Along with the increase in innervation, functional rearrangements also occur that increase dopamine activity in response to external stimuli. Dopamine D1 and D2 receptor density peaks during this period before being pruned back in adulthood. Dopamine receptors increase by 38%, plateau during puberty, and are ultimately pruned 33% in adulthood in the rat. Cyclic AMP levels are 35% higher during adolescence than adulthood. This enhancement of dopamine function during puberty may be partly related to the simultaneous loss of regulatory processes. Although poorly understood, modulation of dopamine synthesis in the prefrontal cortex wanes during pubertal onset and is absent by adulthood. Taken together, the cortical dopamine system rapidly reaches an adultlike state during this time. Circuitry within these regions becomes increasingly complex, as innervation from the dopaminergic cell bodies and other neurotransmitter systems continues during puberty. Connections between stress-related brain regions also become more adultlike during puberty. Once the perception of stress has occurred, activational systems, such as glutamatergic efferents to various emotional and cognitive brain regions, are responsible for the course of action. Sex Differences in the Dopamine System during Puberty
Sex differences exist in the immature dopamine system. It is often the case that females overproduce (and prune) less than males. Dopamine receptors are overproduced in the striatum of males during puberty, whereas little change in either D1 or D2 receptor density is observed in females. The pruning of D1 and D2 receptors shows that density changes by 54% and 63%, respectively, in the striatum, and approximately 25% in the accumbens of males between 40 and 80 days of age. This is not to imply that females do not significantly reorganize during adolescence. For instance, signaling mechanisms, including cAMP, in females are elevated during this period before pruning in adulthood. In preparation for reaching sexual maturity, levels of the gonadal hormones estrogen and testosterone rise in the prepubescent subject. However, their dramatic rise seems to have little impact on the neuroanatomy of the dopamine system. Given the profound sex differences that exist in the dopamine system, it is plausible to hypothesize that testosterone increases the overproduction of dopamine receptors or that
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estrogen suppresses it. Neither seems to be the case. Estrogen in adults or cell cultures increases dendritic branching, yet neuroanatomical changes in female adolescents are not observed. Based on immunohistochemistry with tyrosine hydroxylase antibodies (a marker that stains the rate-limiting enzyme in dopamine production), dopaminergic innervation of the three major terminal fields does not change with age in females. In addition, removal of the gonadal hormones well before they surge does not alter dopamine expression. These data suggest that gonadal hormones are not involved in the activational phases of changes within the dopamine system. Rather, sex differences may be organized during the prenatal period.
Stress Reactivity during Puberty The Hypothalamic–Pituitary–Adrenal Axis and Stress Response
In order to understand stress reactivity, it is necessary to step back and briefly discuss the maturation of the hormonal system of stress responses. The hypothalamic–pituitary–adrenal (HPA) axis is involved in the secretion of stress hormones. Activation of the paraventricular nucleus of the hypothalamus (PVN) is involved in the release of corticotropin-releasing hormone (CRH), which activates the cascade of stress-related changes at the hormonal level. The PVN receives dopaminergic innervation, and thus is modulated by higher-level processing of stressors. CRH travels to the pituitary, causing the release of adrenocorticotropin hormone, which ultimately signals the release of the stress effector hormone cortisol (human and nonhuman primates) and corticosterone (rodents) from the adrenal glands. Cort (abbreviated as such to capture both hormone versions) then travels back to the brain to signal stressrelated changes. The onset of puberty is a transition point in HPA reactivity. Cort activation following acute restraint stress is more pronounced and prolonged in adolescent than in adult rats. Adolescent rats secrete more Cort in response to acute restraint stress than adult rats. Moreover, the response is larger in female than male adolescent rats. The Cort response following chronic stress, however, differs between adolescents and adults. Adolescent rats with a history of chronic stress exposure return to baseline levels faster than adults. Age differences in stress-related reactivity are observable with c-fos immunoreactivity in the PVN. c-fos is often used as a marker of neuronal activity and can be used to map where changes occur. Prepubertal male rats have increased c-fos immunoreactivity
in CRH-containing neurons of the PVN relative to adults in response to an acute stressor. These findings suggest that the prepubertal rat is more sensitive to the effects of stressful events than adults. They also raise the issue of what is initiating this cascade of stressrelated effects.
Dopamine Systems and Stress Responsiveness Of the three primary ascending dopamine systems, the mesocortical dopamine system is the one commonly associated with stress responses. The prefrontal cortex has an abundant amount of glucocorticoid receptors, second only to the hippocampus, which makes the prefrontal cortex particularly vulnerable to stress and its cascade of effects. In adults, stressors including footshock, restraint, and hotplate preferentially increase dopamine release in the prefrontal cortex. The nucleus accumbens is also activated by these stressors, but to a lesser extent than the prefrontal cortex. The striatum is minimally activated in response to acute stressors, but may be more involved in long-term compensations involving habits. Stress Reactivity in the Dopamine System Emerges with Age
It is during pubertal onset that the cortex becomes increasingly vulnerable to the acute effects of stress relative to younger and older ages. Evidence from a pharmacological stressor, the GABAergic antagonist FG-7142, demonstrates that neuronal activity within the three major dopamine systems shifts in dominance. In this study, changes in the immediate early gene c-fos were quantified following FG-7142 and converted to a percentage of total c-fos immunolabeled neurons to derive an index of maturation. The subcortical structures are significantly activated before puberty and may be more vulnerable to stress at this age. These younger animals do not show the adult-typical pattern of dominant prefrontal cortex activation. Not surprisingly, the adult-typical pattern matures between 18 and 45 days of age in the rat – coincident with the onset of puberty. Further, c-fos immunolabeling is enhanced in the prefrontal cortex at 45 days of age relative to adult rats, demonstrating that an acute stressor during adolescence has a greater impact on cortical structures than comparable exposure in adulthood. These findings offer a neurochemical explanation for why children are more likely to increase their activity levels in response to stress. In contrast, as cortically based stress reactivity emerges, adolescents and adults experience stress on a more cognitive basis.
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depressive-like behaviors in rats. This test was designed to parse controllable from uncontrollable stress effects, and relies on cortical modulation. Normal, pubertal female rats demonstrate a higher level of helplessness following one day of conditioning to a series of escalating tail shocks. This sex difference was reversed, however, following a 5-day social stressor that occurs immediately before the onset of puberty. After this subchronic stress exposure, males demonstrate increased learned helplessness, whereas females show some degree of improvement in this behavior.
Circuits Involving Dopaminergic Modulation of Stress
Prefrontal cortex The functional nature of the prefrontal cortex places it in a vulnerable niche. The cortex is involved in motivation and cognition, in part by integrating environmental and emotional information and deciding the next course of action. As an example, abnormality or immaturity of the system is associated with impulsive or inappropriate decisions for a given context. The cortex, however, does not act alone. Connections to other brain regions play a critical role in stress responses during puberty. One such circuit loop is the prefrontal cortex to dorsal raphe. Here, the prefrontal cortex has the important role of differentiating controllable from uncontrollable stress (Figure 2). The learned helplessness paradigm models
The amygdala also plays an important role in stress responses, but more at the level of mediating fear responses. Fear, by definition, is a reaction to a future,
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Figure 2 Learned helplessness paradigm. The learned helplessness model of depression is based on the differential response of rats to (a) controllable shock, (b) uncontrollable shock, or (c) no shock. Controllable (escapable) shock rats can terminate the tail shock by completing a behavioral response (turning a wheel). Uncontrollable (inescapable) shock rats are yoked to the controllable shock rat, so they receive the same number and duration of shocks, but are unable to control the termination of each shock. No shock rats are restrained similarly to the other two rats, but receive no shock during the training phase. The latency to escape a footshock (out of 30 s) and the number of escape failures (out of 30 trials) are recorded in a shuttlebox the next day. Leaned helplessness is defined as longer latencies to escape (f) and a greater number of escape failures than the controllable shock animals (A) or no shock controls (C). The anatomical circuit involved in dissociating controllable from uncontrollable stress involves the prefrontal cortex (PFC) and dorsal raphe nucleus (DRN). (d) Following controllable stress, glutamatergic projections from the PFC act on GABAergic interneurons in the DRN to suppress activation of serotonergic neurons. (e) Following uncontrollable stress, there is an increase in activation of serotonergic (5-HT) DRN neurons that project to the PFC, which serves in part to inhibit the glutamatergic neurons projecting back to the DRN. In the case of either controllable or uncontrollable stress, dopamine (DA) from the ventral tegmental nucleus (VTA) serves to signal the presence of a stressor. This figure and description is based on the seminal work of Maier and colleagues: Amat J, Baratta MV, Paul E, Bland ST, Watkins LR, and Maier SF (2005) Medial prefrontal cortex determines how stressor controllability affects behavior and dorsal raphe nucleus. Nature Neuroscience 8: 365–371.
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probabilistic event based on past, conditioned responses. As such, fear responses are highly dependent on the context. Dopamine, via innervation from the VTA, plays an important role in the plasticity that underlies the associations between the context and the unconditioned, fear-eliciting stimulus. Increases in cortical dopamine are correlated with increased anxiety that increases during puberty. How levels or innervation of the amygdalar dopamine system change in response to stress during puberty is not known and remains another area of future investigation. More is known, however, on the innervation of fibers from the amygdala to the prefrontal cortex. The prefrontal cortex receives input from the amygdala to integrate environmental contextual information with emotional processing. This innervation occurs throughout postnatal brain development, but begins to plateau during the onset of puberty. Studies with systemic and microinjections of dopamine agonists, in addition to dopamine depletions, show that these effects are modulated by dopamine. Again, the developmental profile of this effect is not known. Synthesis
Taken together, data from Cort changes, c-fos localization, and behavioral paradigms suggest that the responses to stressful events rapidly shift during puberty onset. Increased dopaminergic activity in the prefrontal cortex is likely to play a significant role in the processing of environmental events, and thus facilitate enhanced responsiveness to stressful events. Acute stress during puberty onset has a greater impact on females compared with males. However, chronic stress exposure immediately before testing changes this relationship. Males have increased responsiveness within the HPA axis and in learned helplessness following chronic stress exposure when challenged during the pubertal period. The effect on adolescents is short lived, and animals show a return to baseline faster than adult cohorts. Studies such as these further suggest that the stress system is programmed by previous experiences differently during development when compared with adults.
Programming of Immature Stress-Responsive Systems Sensitive Periods of Development
As discussed above, the brain develops in a series of stages. Overproduction and pruning of synaptic connections and signaling mechanisms program the brain to match the demands of the environment. What this means is that stress responses are appropriate for the
level of stress that one has experienced. The immature brain, in turn, encodes these demands by pruning appropriately. However, the timing of stress experiences significantly influences which brain areas are vulnerable. Brain areas undergoing the most change are likely to be affected by stress exposure to a greater degree than those that have yet to overproduce connections or have already pruned. These periods of selective vulnerability are known as sensitive periods. The impact of stressful events on the immature brain will depend on the sensitive period during which the stressor occurred. Early Postnatal Stressors and Brain Development
In order for something to be perceived as stressful, it has to involve the manipulation of something that is highly relevant to the organism. During early postnatal life, one of the single most important variables is the level of parental (predominantly maternal) care. Therefore, it should not be surprising that manipulation of the level of maternal care significantly affects the maturation of stress-related systems. All mammalian species studied to date that have significant variations in maternal care experience changes in Cort responses later in life, although exceptions occur for individual differences. Events set in motion early in life program the formation of brain anatomy and functional impact follows suit. While detailed timecourses of functional changes within the dopamine system have not been assessed during puberty, it is likely that the impact of early life events manifests during this period. Rats have been the most-studied species in maternal deprivation paradigms, and the discussion here will be limited to rodent studies. Early maternal deprivation alters the overproduction of synapses that occurs during adolescence. The most vulnerable region affected is the hippocampus, which fails to overproduce synapses between puberty and adulthood in animals that were stressed early in life. Early stress, however, has little impact on the dopamine system in the prefrontal cortex. The nucleus accumbens shell, on the other hand, fails to overproduce dopaminergic terminals between puberty and adulthood in maternally deprived animals. Dopamine D1 receptors are elevated in the accumbens, with no observable change in the striatum during puberty. The rest of the results that are discussed are based on adult outcomes of the deprivation. Maternal deprivation decreases the density of dopamine transporters in the accumbens. This may explain why cocaine-stimulated dopamine release is higher in these animals. To compensate, animals with a history of maternal deprivation will self-administer
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more cocaine relative to controls in adulthood. As the propensity that stimulant abuse in humans emerges during the adolescent period, these changes most likely emerge during this period. Late Postnatal Stressors and Brain Development
The alternative paradigm to early maternal deprivation involves social isolation beginning from the time of weaning (prepubertal) into adulthood. This paradigm produces a number of behavioral changes linked with reduced cortical dopamine that include deficits in sensorimotor gating of the acoustic startle response, increased locomotion in response to novelty, and enhanced dopamine levels in the prefrontal cortex. Since this paradigm spans across puberty into adulthood, it is difficult to speculate as to when this social stressor exerts its effects on the dopamine system.
Clinical Impact of Stress during Puberty The transition between childhood and adolescence is a unique period of vulnerability. It is during this period that adolescents (males more so than females) engage in risky behaviors, novelty-seeking, and peerdirected behavior including the abuse of substances. Postpubertal changes also serve as a permissive factor for the expression of mental illnesses that are associated with stress, including schizophrenia and depression. For example, stressful events during adolescence often precipitate the first psychotic episode, which on average occurs in males an average of 6 years earlier than in females. Traumatic stress also effects adolescent transitions in brain development, especially within the latedeveloping prefrontal cortex. Exposure to stress is associated with an increase or a decrease in the size of this region, if the timing of the exposure is before or after puberty, respectively. In clear-cut cases of significant, traumatizing, stress, males are affected more than females as cognition is often impaired. For females, the onset of puberty brings with it its own unique challenges. As social roles are defined, the emergence of mood disorders affects females 2.3-fold more than males and rises from 3% of the population to an estimated 8% during adolescence. It is possible that stress during puberty affects the amygdala/cortical development in females, which would increase depression and anxiety. Part of the emerging role of the prefrontal cortex during this time is to modulate stress responses. Mentally healthy individuals are able to separate stressors into these two categories of controllable and uncontrollable and deal with them accordingly.
In contrast, individuals with depression, anxiety, and schizophrenia perceive most stressors as uncontrollable and become overwhelmed (Figure 2). These disorders are associated with elevated levels of cortical dopamine activity in response to stress. The parallel timing of the significant rise in dopamine activity and the prevalence of these disorders during puberty is more than just coincidence. Although this has yet to be demonstrated conclusively, it is likely that increased cortical dopamine plays a role in the perceptual ‘switch’ between controllable versus uncontrollable stress. On the other hand, the pubertal transition, dopamine, and its relationship to stress provide a window of opportunity for some. The waning of motor tics in Tourette’s syndrome during puberty reflects the benefit of positive changes associated with enhanced dopamine activity in the cortex. Generally, tics are exacerbated in response to stress in Tourette’s syndrome patients. The prevalence of tics (or their willful modulation) improves during adolescence.
Conclusions Despite the universal nature of the stressful transitions that are associated with the onset of puberty, relatively little research has been conducted on this important topic. The emerging role of cortical dopamine increases the perception of stress during puberty. Whether this translates into more or less controllability over life’s strife and stress most likely depends on genetic and stress history. What is becoming increasingly clearer, however, is that events that happen before this transition can drastically shape the ability to deal with stressful events later on. The occasion to intervene during this potential window of opportunity beckons more researchers to explore what this area may offer. See also: Stress and Cognition; Stress and Suicide; Stress and Vulnerability to Brain Damage; Stress Response: Sex Differences; Stress Response and Self-Esteem; Stress, Sex and Adolescent Nicotine Response; Stress, Cytokines and Depressive Illness; Stress, the HPA Axis and Depressive Illness; Stress: Definition and History; Stress: Homeostasis, Rheostasis, Allostasis and Allostatic Load.
Further Reading Amat J, Baratta MV, Paul E, Bland ST, Watkins LR, and Maier SF (2005) Medial prefrontal cortex determines how stressor controllability affects behavior and dorsal raphe nucleus. Nature Neuroscience 8: 365–371.
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