The adolescent brain and age-related behavioral manifestations

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Abstract

To successfully negotiate the developmental transition between youth and adulthood, adolescents must maneuver this often stressful period while acquiring skills necessary for independence. Certain behavioral features, including age-related increases in social behavior and risk-taking/novelty-seeking, are common among adolescents of diverse mammalian species and may aid in this process. Reduced positive incentive values from stimuli may lead adolescents to pursue new appetitive reinforcers through drug use and other risk-taking behaviors, with their relative insensitivity to drugs supporting comparatively greater per occasion use. Pubertal increases in gonadal hormones are a hallmark of adolescence, although there is little evidence for a simple association of these hormones with behavioral change during adolescence. Prominent developmental transformations are seen in prefrontal cortex and limbic brain regions of adolescents across a variety of species, alterations that include an apparent shift in the balance between mesocortical and mesolimbic dopamine systems. Developmental changes in these stressor-sensitive regions, which are critical for attributing incentive salience to drugs and other stimuli, likely contribute to the unique characteristics of adolescence.

Introduction

The central thesis of this review is that maturational changes in brain contribute to the age-specific behavioral characteristics of adolescence, including an increase in propensity to use drugs. Certain behavioral features common among adolescents of a variety of species may have evolved to promote attainment of the necessary skills for independence; these age-related behaviors, such as an adolescent-associated increase in risk taking, may be promoted less by increases in pubertal hormones than by developmental events occurring in brain during adolescence. These age-related neural alterations provide a partial biological basis for the unique behavioral strategies of adolescence, although they are not deterministic. Rather, these transient neuronal features may predispose adolescents to behave in particular ways, and make them particularly likely to initiate use of alcohol and other drugs relative to individuals at other ages.

The focus of this review is on adolescence rather than the more temporally restricted phase of puberty. Although the timing of these periods overlap, the terms are not synonymous. Puberty refers to the attainment of sexual maturation (i.e. gonadarche) [210]. In contrast, adolescence is the gradual period of transition from childhood to adulthood, and thus is a process or series of “soft events” [422] rather being defined by a discrete event or events. As such, it is difficult to characterize the precise onset and offset of adolescence. Although “one may define puberty in specific neuroendocrinological terms,…adolescence is, of its essence, a period of transitions rather than a moment of attainment” ([468], p. 63). Puberty is but one of these adolescent transitions. In humans, the onset of the biological changes associated with puberty often has been considered to signal the onset of adolescence (e.g. Ref. [409]), although the timing of puberty within the adolescent period varies notably among human adolescents (e.g. Ref. [144]). Indeed, the timing and tempo of puberty may be of considerably psychosocial significance for adolescent humans, with early maturation advantageous in several respects for boys but associated with several negative outcomes for girls (see Ref. [212] for review and references).

Developing mammals of many species undergo an ontogenetic transition from the dependence of youth to the (relative) independence of adulthood. During this transition, individuals across a variety of species undergo puberty and are faced with similar developmental challenges of acquiring the necessary skills to permit survival away from parental caretakers. As discussed later in this review, human adolescents and many of their counterparts in other species exhibit certain characteristic behaviors, including increases in peer-directed social interactions and elevations in novelty-seeking and risk-taking behaviors. These transient behavioral features may represent ontogenetic adaptations [391] to help adolescents survive in the limbo between childhood and adulthood, while also serving to assist them in acquiring the necessary skills to permit survival away from parental caretakers. Increased affiliation with peers and the taking of risks via exploring novel areas, behaviors and reinforcers may also help facilitate the dispersal of adolescents away from the natal family unit. Such an age-related emigration is common among mammalian species (even humans in pre-industrial societies—see Ref. [518]) and may have been evolutionarily adaptive as a means to avoid inbreeding [484].

Although there are many gaps in our knowledge of ontogenetic changes in brain function during adolescence, the data that are available suggest that prominent neural alterations in brain regions such as prefrontal cortex (PFC) occur during adolescence not only in humans, but across species ranging from rodents to nonhuman primates (see later discussion). Given these across-species similarities in neurobehavioral features of adolescence, the question arises as to whether nonhuman animals undergoing this developmental transition can be used as models of human adolescence.

Some researchers have argued that adolescence is uniquely human and hence cannot be modeled in animals (e.g. Ref. [50]). For instance, Bogin [50] maintains that only humans undergo adolescence based on the conclusion that only human adolescents show a growth spurt [571]. Yet, developmental hyperphagia and accelerated growth rates are evident during adolescence even in adolescent rodents (e.g. Ref. [283]). Indeed, others have concluded that pubertal growth spurts are common across mammalian species, and it is the relatively long period of slowed growth during the preadolescent childhood/early juvenile period that is unique to humans and other primates [587]. Reasoning for the exclusivity of human adolescence based on growth criteria alone can also be challenged by questioning whether the global attribute of adolescence should be affirmed or dismissed solely on the basis of any single characteristic.

There are many different processes unfolding during adolescence, and what one identifies as essential feature(s) of adolescence determine the appropriateness of any given animal model. Traditionally, animal models have been extensively used for the purposes of modeling human psychopathology, with each given animal model typically emulating only a few psychopathological features thought to be central to the target disorder. Certainly no animal model can be similar in all respects to the complexity of human psychopathology or of human behavior during adolescence (or at any time in life, for that matter). Indeed, there are numerous areas of adolescent functioning in humans that seemingly cannot be addressed using animal models, including issues ranging from peer pressure and self esteem, impact of parenting styles on parent/adolescent conflict, obsessions with thinness in adolescent females in some Western cultures, and cultural differences in perception of adolescence as a life stage, to mention but a few.

Thus, as with animal models of psychopathology in humans, to answer the question of the appropriateness of animal models of adolescence, it is necessary to first consider what aspect of human adolescence is to be modeled. For instance, the increases in adrenal androgens/neuroactive steroids seen during adrenarche in humans (see later section of this review) are generally not evident in other mammalian (or even primate) species. Chimpanzees are an exception (e.g. Ref. [111]), and hence may provide a useful model to examine effects of adrenarche on subsequent neurobehavioral and endocrine function during adolescence. As another example, given that much information about neural substrates and hormonal factors modulating drug self-administration has been obtained in rodent studies, work in rodents may provide a cost-effective model to examine neurobehavioral characteristics underlying the rewarding effects of drugs, social stimuli and their environmental modulation during adolescence. Yet, forebrain systems of rodents are substantially less prominent than in humans and other primates, their social organization considerably less complicated, and the time course of their adolescence brief; these and other limitations add constraints to the use of rodent models. The more protracted development of nonhuman primates and their generally more complex social structure relative to other laboratory animals may prove useful for long-term studies of pharmacological and social environmental influences on drug self-administration during adolescence, although more needs to be understood regarding the time course of adolescence in nonhuman primates, particularly among seasonal breeders where the onset of puberty per se is often tightly synchronized with the mating season (e.g. [95], [427]).

The validity of animal models is typically assessed using three evaluation criteria borrowed from the psychological testing literature [361], [592] and adapted for assessing the validity of animal models of human psychopathology (e.g. Ref. [595]). Face validity asks whether there are similarities between the model and what is being modeled in terms of etiology, symptomology, treatment, or physiological bases. Predictive validity examines whether the model successfully forecasts future findings (typically regarding efficacy of drug treatments). Construct validity addresses whether the model is homologous to the clinical syndrome being modeled in terms of physiological determinants, precipitating psychosocial environment and other factors theorized to influence its occurrence [595]. As discussed later in this review, there are similarities between human adolescents and various animal models of adolescence in terms of developmental history, behavioral symptomology as well as neural and hormonal characteristics. These resemblances provide some measure of face and construct validity that are sufficiently promising to support further development of these animal models as tools for the study of adolescence. Assessment of validity is an ongoing process; as more data is generated, stronger tests of these forms of validity as well as that of predictive validity will be possible. Ultimately the validity of animal models is determined by their usefulness in expanding understanding of the phenomena under investigation, propagating further testable hypotheses, and generating data to refine the model and further assess its validity.

Adolescence eludes precise characterization of its ontogenetic time course, with no single event signalling its onset or termination. There are numerous physiological and sociobehavioral transitions that occur during the age span between childhood to adulthood, with the timing of these transitions varying with nutritional status [181], [284] as well as sociocultural values and economic conditions in humans [155]. For the purposes of this review, adolescence in humans will be considered to be the age range from roughly 12 to 18 years, ages commonly considered to be within the adolescent age span in humans. There is less consensus as one approaches the “gray zones” at the margins of this age range. The entire second decade is not infrequently considered adolescence (e.g. Ref. [412]), and even ages up to 25 years have been considered as late adolescence by some researchers [35]. Conclusions reached regarding the boundaries of adolescence may vary depending not only on the adolescent transition of focus, but also gender, with females across mammalian species generally maturing more rapidly than males (e.g. Ref. [483]).

When assessing the time frame of adolescence in nonhuman animals such as the rat, it likewise is difficult to characterize absolute boundaries during which the first transition of adolescence begins to emerge and the last remnant still persists. Even among the handful of researchers who study adolescence in rats, opinions somewhat differ. Not only may the boundaries vary with gender, the transition under examination, and the growth rate of animals derived from different suppliers, but the problem is further magnified by the limited amount of research that has focused on adolescence in laboratory animals. Although much research in nonhuman animals has been directed toward the neuroendocrinology of puberty and potential triggers of these changes, relatively little animal research has been intentionally directed toward examination of biosociobehavioral function during the broader age range of adolescence. For instance, in developmental work with rats, researchers have often tested animals up until the conventional age of weaning and again in adulthood, drawing a straight line between these points. Adolescence in nonhuman primates is even less explored territory [407], [408].

Rather than engaging in a questionable and premature attempt to define the absolute margins of adolescence, the strategy used in this review will be to characterize prototypic adolescence in rats using a conservative age range during which animals of both genders and most breeding stock would be expected to exhibit adolescent-typical neurobehavioral characteristics. This age range from approximately postnatal days 28–42 (P28–42) was originally derived by considering the age range during which age-specific behavioral discontinuities from younger and older animals were evident (e.g. Ref. [510]), but is also supported by measures as diverse as the timing of the growth spurt (peak at 4–5 weeks of age—e.g. Ref. [283]; Silveri and Spear, unpublished observations), the loss of excitatory amino acid overshoot to PFC (developmental peak in N-methyl-d-aspartate [NMDA] receptor binding at P28 at levels that are substantially higher than at P60 [253]), and the timing of emergence of rats from the protected nest burrow in the wild (beginning at P28— Ref. [186]). During this interval, vaginal opening occurs in females [137] and marked increases are seen in the number of maturing spermatids in the seminiferous tubules in males [93].

Use of this conservative age range is not meant to imply, however, that animals in the gray zone slightly younger or older than this prototypic age range might not also be undergoing some adolescent transition(s). Indeed, some ontogenetic changes signalling the early onset of adolescence in female rats may begin to emerge as early as 20 days, with later changes lasting until 55 days or so in males [387], [390]. The latter is important to recognize, given that 250–275 g male rats are sometimes used in work presumed to examine neurobehavioral function in adults, although males in this weight range may fall within the gray zone between adolescence and adulthood. Under some experimental circumstances, inclusion of a broader age range of adolescence (e.g. from shortly after weaning until 60 days or so) may be prudent if the intent is to expose animals to a particular treatment throughout the entire ontogenetic window from the emergence of early harbingers of puberty in females through the disappearance of the last of these changes in males. With additional research examining adolescence in rodent models, new findings regarding the timing of particular developmental transitions within the adolescent period may help to further characterize the limiting boundaries of this stage of life.

If anything, the timing of adolescence in nonhuman primates is even less established, with some primate researchers even avoiding use of the term. Those that do typically consider adolescence to be the time between puberty and mature reproductive function [405], [406] or the time from first external signs of impending sexual maturity to the cessation of linear growth [582]. Dentation and hormone levels have also been used to accurately determine adolescent stage, although these measures require more invasive assessments than are typically available in naturalistic settings [300].

More commonly employed than the term “adolescence” in studies with nonhuman primates is the term “juvenile” that has been varyingly used to refer to the age span from weaning until puberty [404], until sexual maturity (typically defined by successfully carrying offspring to term) [105] or until physical growth rate begins to slow [259]. Researchers using puberty as a stage discriminator typically also include a “sub-adult” period consisting of postpubertal but prereproductive individuals (e.g. Ref. [150]). The distinction between puberty and sexual maturity is important here; following menarche, female primates typically undergo a period of “adolescent sterility” before beginning to ovulate regularly (e.g. [46], [459]). High teen pregnancy rates not withstanding, human females also typically show depressed fertility during early adolescence [257], with as much as 5 years being required after menses begin for mature rates of ovulatory frequency to be reached [601]. As is the case with their female counterparts, nonhuman primate males typically do not father young at puberty, but first must attain a certain status via emigration and/or attainment of high rank among conspecifics (see Ref. [408] for discussion).

Researchers do not always agree on the timing of the juvenile and adolescent stages among specific primate species (e.g. compare the timing of adolescence in rhesus monkeys presented by Ehardt and Bernstein [150], with that of Paule [399]), perhaps in part because of variations in the indices used to reflect maturational state, and sensitivity of maturational rate to environmental quality. The latter includes variables such as nutrition, social context, stress, energy drains and other factors that may vary among primate populations [601], particularly those studied in captivity versus in the wild [259], [366]. The rather long time span characterizing the juvenile period as typically defined in primate research corresponds in humans to roughly the interval from 2 years of age until 13–25 years—i.e. childhood and much or all of adolescence [601]. Thus, what appears to be comparable to the adolescent period in humans encompasses latter portions of the juvenile period in primates (classified as “older juveniles” by some) as well as part of the subadult period when included as a separate stage. These time periods will be referred to as “adolescence” for the purposes of this review, whether or not so-referred in the material cited.

Section snippets

Adolescent behavioral changes

For successful negotiation of the developmental transition from childhood to adulthood, developing organisms must attain the necessary skills for independence. Behavioral characteristics of adolescents that bear similarity across diverse species may have adaptive value [483] and may represent ontogenetic adaptations to meet the needs of this age-specific niche [391] as well as the means by which necessary adult skills are acquired. An adolescent-associated increase in risk taking is seen in a

Adolescent drug use

High levels of novelty/sensation-seeking are powerful predictors of drug and alcohol use [17], [35], [597]. Hence, it perhaps should not be surprising that along with increases in sensation and novelty seeking during adolescence [24], [342], [369], an increase in drug use is seen as well.

Stress and adolescence

Given the large number of transitions faced by adolescents, they have been viewed to be “…in a chronic state of threatened homeostasis,” with “their adaptive responses during this period (being) crucial” ([141], p. 685). Stress likewise has been characterized as a state of threatened homeostasis that requires adaptive processes to restore and sustain this equilibrium. Thus, almost by definition adolescence could be considered to be a stressful life stage. Indeed, Denver [122] has postulated

Hormonal changes of adolescence

In addition to developmental alterations in stress-induced HPA activity discussed previously, two characteristic types of hormonal changes are associated with adolescence: adrenarche, the increase in output of adrenal hormones that begins to occur prior to other signs of impending adolescence; and gonadarche, the pubertal increase in gonadal hormones associated with the process of sexual maturation. These hormonal changes and their behavioral implications will be briefly reviewed prior to

Neural alterations during adolescence

Impetus for assessment of neural development during adolescence has largely arisen from two quarters, one of which was just reviewed. In addition to these studies that have largely focused on hypothalamic areas and puberty, interest in forebrain regions during adolescence was precipitated by observations that the symptomology of psychological disorders including depression (e.g. see Ref. [302]) and schizophrenia (see Ref. [584] for review) typically increases substantially during adolescence.

Summary and final comments

Over the past several decades, research in developmental psychology has placed surprisingly little emphasis on adolescent brain in the quest for determinants of adolescent-typical behavioral propensities. Yet the adolescent brain is a brain in transition, and differs anatomically and neurochemically from that of the adult. Although the data in some cases are still limited, this remodelling of brain during adolescence appears highly conserved across species and may involve age-specific

Acknowledgements

Preparation of this review was supported in part by K02 DA00140 as well as R01 grants AA10228, AA12150, AA12525, and DA04478. Special thanks to Patti Heebner for her invaluable assistance in reference management and manuscript preparation, Marisa Silveri for her help in preparation of the figure, and the Binghamton University library system for their continued support, excellent journal and book holdings, and indispensable accessing services.

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