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Review Pubertal onset as a critical transition for neural development and cognition

Janice M. Juraska n, Jari Willing

Department of Psychology and Neuroscience Program University of Illinois, 603 E. Daniel St., Champaign, IL 61820, United States article info abstract

Article history: Adolescence, broadly deﬁned as the period between childhood and adulthood, is characterized by a Received 31 December 2015 variety of neuroanatomical and behavioral changes. In human adolescents, the cerebral cortex, especially Received in revised form the prefrontal cortex, decreases in size while the cortical white matter increases. Puberty appears to be 2 April 2016 an important factor in both of these changes. However, the white matter continues to grow beyond what Accepted 5 April 2016 is thought to be adolescence, while the gray matter of the cortex stabilizes by young adulthood. The size changes that are the manifestation of cortical reorganization during human adolescence are also seen in Keywords: cellular reorganization in the rat cortex. The prefrontal cortex loses neurons, dendrites and synapses Prefrontal cortex while myelination in the white matter continues to increase. All of this reorganization is more marked in Adolescence female rats, and there is evidence both from pubertal timing and from removal of the ovaries that Puberty puberty plays an important role in initiating these changes in females. The maturation of behavioral Neuron number Inhibitory control functions of the prefrontal cortex, such as inhibitory control, occurs in both humans and rats across adolescence. There is also evidence for puberty as a major factor in decreasing perseveration in rats, but few studies have been done using pubertal status as an experimental variable, and the role of the gonadal steroids in modulating behavior throughout life makes clear effects more difﬁcult to document. In all, puberty appears to be so essential to the changes occurring during adolescence that it should be recorded when possible, especially given the sex difference in pubertal timing. This article is part of a Special Issue entitled SI: Adolescent plasticity. & 2016 Published by Elsevier B.V.

Contents

1. Introduction...... 1 2. Neural development during adolescence ...... 2 2.1. Humans...... 2 2.2. Rats ...... 2 3. Hormonal effects during adolescence...... 4 3.1. Hormone receptors ...... 4 3.2. Hormonal effects in humans...... 4 3.3. Hormonal effects in rats ...... 5 4. Behavioral changes and hormone effects ...... 5 4.1. Adolescence ...... 5 4.2. Puberty...... 6 5. Conclusions ...... 6 Acknowledgments...... 7 References...... 7

1. Introduction

Adolescence is the period between childhood and adulthood, n Corresponding author. characterized by neural maturation and changes in a variety of E-mail address: [email protected] (J.M. Juraska). cognitive behaviors in addition to reproductive behavior. While it http://dx.doi.org/10.1016/j.brainres.2016.04.012 0006-8993/& 2016 Published by Elsevier B.V.

2. Neural development during adolescence

2.1. Humans

Several MRI studies have indicated that the human cerebral cortex decreases in size during adolescence (Jernigan et al., 1991; Giedd et al., 1999; Sowell et al., 1999). While this appears to occur across many cortical areas, the prefrontal cortex (PFC) has the most reliably large decrease (Sowell et al., 2003; Gogtay et al., 2004), and this is especially interesting given that behaviors mediated by the PFC in particular undergo maturation during this time (Durston and Casey, 2006). There was a report that synaptic density in the PFC decreases during adolescence although the number of subjects and ages examined are very small (Huttenlo- cher, 1979). Still there is some supporting data from macaques (Bourgeois et al., 1994) and through quantiﬁcation of the synaptic marker, synaptophysin, in the human PFC with Western blots (Glantz et al., 2007). While all of these studies contained both male and female subjects, only Giedd et al. (1999) described different trajectories in cortical maturation between the sexes. Giedd et al. noted the peak of cortical size could be affected by puberty; Fig. 1. The number of neurons in the rat mPFC at postnatal ages that encompass other investigators did not have the statistical power to draw such adolescence. (A) Females lost neurons between P35 and P45, and the average age of pubertal onset was P35. *po.05. (B) Unlike the females, males only showed a inferences. nonsigniﬁcant trend (po.08) for age. From Willing and Juraska (2015).

2.2. Rats number of neurons in the mPFC occurred between P35 and P45 The volume of the medial (m) PFC peaks and decreases across (Fig. 1A). adolescence (Van Eden and Uylings, 1985) in rats as it does in Dendritic pruning has also been found between adolescence humans, and thus rats have been the subjects for more detailed and adulthood in layer 5 pyramidal neurons in the mPFC (Koss cellular analyses of neuroanatomical changes in the PFC. Adoles- et al., 2014). Both males and females had a decrease in dendritic cence has been previously defined as postnatal days (P) 28–42 spine density between P35 and P90 (Fig. 2), and females also lost (Spear, 2000). Spear admitted that this definition is arbitrary, and dendritic branches, indicating an even greater decrease in the total we would argue on the basis of the timing of puberty and its number of dendritic spines. Interestingly, both dendritic spines importance for adolescence (the topic of this review) that it be and the total length of the dendritic tree increased in both sexes extended beyond P42. This is especially true for male rats where between P20 (the juvenile period) and P35. Thus the dendritic puberty occurs between P40 and P48 (Willing and Juraska, 2015; capacity is at a peak during adolescence in comparison to both Korenbrot et al., 1977). Work from our laboratory has found several juvenile and adult animals. The loss of synapses was confirmed types of pruning between the adolescent period and adults that across the whole mPFC in females through quantification of sy- vary in degree with sex. Markham et al. (2007) found that the naptophysin, a synaptic marker, which decreased between P35 number of neurons decreased between P35 and P90, as did the and P45 in females (Drzewiecki et al., 2015). Changes in afferent volume of the mPFC in females. It should be noted that this was and efferent projections between the mPFC and basolateral the total number of neurons, not just neuron density. The calcu- amygdala (BLA) have also been examined during adolescence in lation of the number of neurons is the density of neurons, obtained males. The number of neurons projecting from the PFC to the basal with the optical disector, multiplied by the volume of the mPFC amygdala decreases from P45 to P90 in male rats, and con- from cytoarchitectonic parcellation. Both sexes lost neurons in the comitantly the number of mPFC axons in the basal amygdala de- mPFC but females had considerably greater losses than males. creases (Cressman et al., 2010). It is not clear whether this is due to Interestingly, the adjacent anterior cingulate showed no differ- neuron pruning during adolescence or to pruning of axon col- ences in either sex between P35 and P90, indicating that not every laterals. This occurs while the number of axons from BLA within cortical area loses cells during adolescence. The large decrease in the mPFC is increasing from the juvenile period into adulthood the number of neurons after P35 in females was further confirmed without a discernable peak in adolescence (Cunningham et al., in Willing and Juraska (2015) where a significant decrease in the 2002).

Fig. 2. The density of dendritic spines at postnatal ages on layer V pyramidal neurons in the mPFC (a) on the basilar dendrites and (b) on the apical dendrites. Spines were pruned between P35 and P90. There were no sex differences. (c) A photograph of dendritic spines visualized with a Golgi Cox stain. *po.05; #po.08 from Koss et al. (2014).

There are also changes in transmitter levels as well as their than in adults in the rat PFC (Insel et al., 1990; Andersen et al., receptors during adolescence in the mPFC, but the picture is not 2000). Additionally, the electrophysiological response to dopa- yet a coherent one. The investigation of transmitter systems has mine within the male mPFC changes during adolescence (O’Don- mainly been done in males, and both NMDA receptor binding nell, 2010) with D2 agonists causing mild inhibition prepubertally (from P28 to oP60) and dopamine receptor (D1 and D2) densities (P36) but strong excitation after puberty (P50). Lastly, the GABA (P40 to P80) were found to be higher in the periadolescent period receptor also alters its composition during adolescence (Smith,

3. Hormonal effects during adolescence

3.1. Hormone receptors

One obvious question is which hormone receptors are present peripuberally in the cerebral cortex, particularly within the mPFC. This very relevant topic has not been directly explored in the ex- isting literature. In the adult human temporal cortex, both males and females have moderate levels estrogen receptor (ER) α and ERβ (González et al., 2007). It is not known if these receptors are present in the PFC or if they are expressed during the pubertal transition. Like estrogen receptors, androgen receptors (AR) are also expressed in the primate and rat prefrontal cortex in adulthood (Finley and Kritzer, 1999; Aubele and Kritzer, 2012). In adult female rats, Shughrue et al. (1997) found moderate levels of ERβ in the mPFC. Although it is not known if they appear peripubertally, Westberry and Wilson (2012) found that in mice of both sexes, ERα decreases between P4 and P25 in the mPFC while ERβ increases. This indicates that ERβ may play a role in the mPFC during puberty. It also should be noted that progesterone receptors in the mPFC decrease after 10 days of age in rats and reach very low levels by P25 (Willing and Wagner, 2015). Thus while the in- formation is incomplete, ERβ is the most likely candidate for mediating effects in the rodent mPFC.

3.2. Hormonal effects in humans

In order to understand the mechanisms behind the numerous cellular changes occurring during adolescence, an essential question is whether these changes are directly due to pubertal hormones or simply chronological age, independent of hormonal activity. There are indications that puberty is necessary for many neuroanatomical changes, although the evidence is circumstantial. Puberty is a protracted event in humans that continues for years. It is assessed through Tanner stage (either physical examination or self-report) and hormone levels, each of which has its limitations (see the discussion in Peper et al., 2011 and Herting et al., 2015). Fig. 3. The number of myelinated axons in the splenium of the corpus callosum The Tanner stages indicate the long term continuation of rising quantified from electron micrographs. Females are clear bars and males stripped hormones that may direct prolonged alterations in neural orga- bars. **po.005; ***po.0005 from Kim and Juraska (1997). nization. These neural changes are difficult to discern except within an individual in longitudinal studies that include the pre- 2013), and this topic will be reviewed elsewhere in this issue pubertal period. Additionally, hormone levels are not only gen- (Shen at al., in this issue). Thus the adolescent rat mPFC undergoes erally increasing over time but also vary on a daily basis, in ad- considerable cellular reorganization much, but not all, of which is dition to the obvious monthly time frame for females. This makes pruning. hormone levels even more unreliable as an indicator of pubertal In addition to local changes in cortical structure, the white status. matter carrying cortical afferents and efferents, including the Nonetheless, the studies that have tracked pubertal status have white matter under the PFC, steadily increases during adolescence found that it is often an important factor for several measures. The in humans and in rat models with males showing larger increases progression in Tanner stages over a 2 year period marked a thin- than females in both species (Giedd et al., 1999; Perrin et al., 2009; ning of portions of the frontal cortex in both males and females Markham et al., 2007; Willing and Juraska, 2015). The cellular (Herting et al., 2015). Tanner stage also predicted decreases in other cortical regions in a sex-specific manner. There were effects basis for this increase appears to be continuing myelination which of hormone levels but they were less definitive than pubertal is supported by evidence from diffusion tensor imaging of humans status (Herting et al., 2015). Likewise, both increasing levels of (Herting et al., 2012). Electron microscopic quantification of axons testosterone and dehydroepiandrosterone (DHEA), an adrenal in the splenium of the corpus callosum from the visual cortex androgen, across adolescence are associated with decreasing cor- confirms that the number of myelinated axons increases during tical thickness in both sexes (Nguyen et al., 2013). Taking a dif- adolescence (Fig. 3). This occurs in both sexes but more axons are ferent approach, Raznahan et al. (2010) found that a more efficient myelinated in males (Kim and Juraska, 1997) while there is no androgen receptor allele was associated with more cortical thin- change in axon caliber within a class (myelinated vs un- ning during adolescence in both sexes, even while sex differences myelinated). This implies that myelination is the basis for the in- persisted in the rate of frontal maturation. The increase in size of creases in the size of all of the cortical white matter. Myelination both the subcortical white matter in males (Perrin et al., 2009) and extends to middle age, albeit at a slower rate, in both humans the corpus callosum in both males and females (Chavarria et al., (Bartzokis et al., 2001; Courchesne et al., 2000) and rats (Nuñez 2014) correlated with testosterone levels. Lastly, the rate of cere- et al., 2000; Yates and Juraska, 2007) and is not a unique feature of bral blood flow has been found to vary with self-reported Tanner adolescence. stage in a sex-dependent fashion (Satterthwaite et al., 2014). In

3.3. Hormonal effects in rats

The cellular basis for the effects of puberty can be explored more precisely in rat models since many of the gross size changes found in humans are also seen in rats, such as decreases in cortical volume and increases in white matter volume (Markham et al., 2007). Puberty can be directly prevented by removing the gonads during the juvenile period which preclude puberty, while avoiding the organizational effects of gonadal hormones during early development. Puberty in rats is relatively rapid with clear somatic markers: vaginal opening that coincides with increased luteinizing hormone output in females (Castellano et al., 2011) and preputial separation that marks increased testosterone secretion in males (Korenbrot et al., 1977). Although there are individual and strain differences in the exact day that puberty is reached, we have found that there is virtually no overlap in the range between males and females within a set of litters born in the same season under the same conditions. This helps disentangle the effects of age from those due to puberty and allows for studies in which monitoring of the pre- and post-pubertal period are clearly delineated. There is considerable evidence that removal of the ovaries before the onset of puberty, usually at P20, stops the pruning within the cortex that occurs in intact females. Ovariectomy (OVX) before puberty resulted in increased numbers of both neurons and glia compared to control females in both the visual cortex and mPFC (Nuñez et al., 2002; Koss et al., 2015)(Fig. 4). There was no evidence of effects of gonadectomy in males in either of these cortical regions. Pre-pubertal OVX also halted the pruning of dendritic spines in the visual cortex of females (Muñoz-Cueto et al., 1990). Females ovariectomized before puberty had a greater volume of cortical white matter under the frontal cortex than intact controls (Koss et al., 2015), and OVX females had more myelinated axons in the corpus callosum (Yates and Juraska, 2008) which appears to be the basis for the increased volume since there Fig. 4. (a) The number of neurons in the two subdivisions of the rat primary visual was no change in the number of axons. cortex (Oc1M and Oc1B) in adult rats. The control females had significantly The results from tracking puberty have supported the findings (po.05) fewer neurons in both divisions than control males and day 20 OVX fe- fi with OVX that the rises in ovarian steroids are the primary cause males. Modi ed from Nuñez et al. (2002). (b) The number of neurons in the mPFC in adult rats. Gonadectomy (GDX) had of many neural changes. The number of neurons in the mPFC of occurred at P20. *po.05 from Koss et al. (2015). intact females decreases between P35 and 45 (Fig. 1A), and the average age of puberty in these females was P35 (range P32-38) (Willing and Juraska, 2015). Counts of GABA immunoreactive in- and P35 than males (Willing et al., 2015; unpublished data; Susan terneurons indicated that proportionately more non-GABAergic Andersen, personal communication). This indicates that puberty, (pyramidal) neurons were lost than GABAergic were lost in these although important for cellular reorganization, is not the sole animals between P35 and P45. Neuron number, in general, was mechanism of neural change during the adolescent period. stable before and after the pubertal transition. Consistent with the findings of Koss et al. (2015), males had only statistically marginal decreases across adolescence with no marked change during 4. Behavioral changes and hormone effects puberty (average age P45) (Fig. 1B). There were indications of synaptic pruning, visualized with 4.1. Adolescence synaptophysin, in both sexes during the pubertal transition in the mPFC, although the data from females was more definitive The adolescent period in humans is known to be associated (Drzewiecki et al., 2015). Synapse quantification came from the with changes in performance on a variety of tasks, especially those same brains as the neuron counts in Willing and Juraska (2015) that are PFC-dependent. Notably, cognitive control, defined as si- and indicates that synapses can be lost without a significant loss of tuationally appropriate behavioral responses in the face of con- neurons. A different pattern was found in these brains with TH flicting ones, improves considerably between the juvenile period staining of afferent axons. TH is the rate limiting step in dopamine and adulthood (see Durston and Casey, 2006). Included within this synthesis and the amount of dopamine can covary with TH levels definition is behavioral inhibition and cognitive flexibility, which (Masserano and Weiner, 1983). In primates, the upper layers of the coincide with a decrease in perseverative behavior. In humans, PFC show some peripubertal pruning of TH fibers (Rosenberg and performance on tasks measuring cognitive control improves from Lewis, 1995). This contrast with rats where TH increased in both childhood to adulthood (reviewed in Lourenco and Casey, 2013; males and females linearly in the mPFC between P25 and P90 with Taylor et al., 2013; Davidson et al., 2006; Casey, 2015). In general, females showing proportionately more of an increase between P25 these improvements manifest in laboratory tasks as increases in

Fig. 5. Path length to reach the novel platform location in the Morris water maze. Path length was significantly lower in post-pubertal males and females in comparison to pre-pubertal after the location of an escape platform was moved. a4b po.03 Modified from Willing et al. (In press). social cognition, concept formation, task-switching, working memory tasks (reviewed in Juraska and Rubinow, 2008; Luine, memory, and the inhibition of inappropriate responses that were 2008; Frick et al., 2010). However, there is little evidence thus far formerly rewarded. It is unclear whether these abilities are im- that puberty itself directly results in developmental changes in proving across adolescence without pubertal influence or are ei- cognitive behavior. Evidence for a direct role for pubertal onset in ther dependent upon or influenced by the neural reorganization of cognition has been particularly difficult to elucidate using certain puberty. cognitive tasks given that puberty has been shown to alter Both humans and mice show attenuated fear extinction during learning strategies in spatial memory/navigation paradigms (Kanit adolescence compared to juveniles and to adults (Pattwell et al., et al., 2000; Rodríguez et al., 2013). In a recent study from our 2012). This task, which involves the PFC, is an illustration of the laboratory (Willing et al., in press), we used pubertal onset as a uniqueness of adolescence that goes across species. There are factor to explore changes in performance in male and female rats other examples of increased performance on PFC-dependent tasks on the water maze and also on a reversal task that assessed cog- between adolescence and adulthood in rats. Compared to adults, nitive flexibility. Pubertal status did not have an effect on short or adolescent rats display a learning deficit on a delayed alternation long-term spatial memory for the location of an escape platform in task and commit a greater number of perseveration errors (Koss the initial training. This is consistent with Schenk (1985) who et al., 2011). Additionally, across several tasks, adolescent rats are found that adolescent rats performed at the same level as adults in less sensitive to extinction or reward devaluation compared with the water maze task. However, when we moved the location of the adults (Sturman et al., 2010; Andrzejewski et al., 2011; Naneix platform, pre-pubertal males and females had an increased path et al., 2012; Hammerslag and Gulley, 2014), suggesting an im- length compared to post-pubertal animals (Fig. 5). Additionally, pairment in impulse control and behavioral inhibition. These during these trials, pre-pubertal rats spent more time in the studies collectively suggest that in both humans and rats, PFC quadrant of the maze where the platform was originally located, maturation during adolescence coincides with decreases in per- which may be indicative of perseverative behavior, than recently severative responding and inhibitory control, functions that are post-pubertal and adult animals. No differences were seen for any dependent on PFC interactions with other parts of the limbic measure between recently post-pubertal and adult rats. This system such as the basolateral amygdala. subtle yet significant effect of pubertal onset suggests that puberty leads to relatively rapid changes in cognitive behavior that may be 4.2. Puberty linked with the neuroanatomical alterations mediated by puberty. Interestingly, with non PFC-dependent tasks, such as basic con- Though not typically examined as an experimental variable, ditioning and spatial memory, pre-pubertal animals are not dif- there is some evidence that pubertal status plays a role in beha- ferent than adults (Stanton and Freeman, 2000; Raineki et al., viors that mature during human adolescence (reviewed in Blake- 2009; Voorhees et al., 2005; Brown et al., 2005; Wojniusz et al., more et al., 2010). Pubertal onset, in particular, seems to trigger an 2013) and in place avoidance pubertal females are impaired (Shen increase in behavioral responsiveness to emotionally salient sti- et al., 2010; Shen et al., in this issue). Future studies examining muli, which is correlated with changes in functional connectivity cognitive behavior during adolescence should account for pubertal between the PFC and subcortical limbic regions (Ladouceur, 2012; status and for the sex difference in the age of pubertal onset, since Klapwijk et al., 2013). Additionally, pubertal status has been shown pubertal status may be at least as important as chronological age. to acutely affect performance on the PFC-dependent match-to- sample task, where pubertal onset actually induced a transient decrease in performance (McGivern et al., 2002), possibly reflect- 5. Conclusions ing ongoing functional changes in PFC anatomy or connectivity. A rise in pubertal testosterone in males has been found to be asso- There is considerable evidence that puberty is a central event in ciated with an increase in mental rotation performance (Vuoksima the reorganization of the cortex, especially the prefrontal cortex, et al., 2012), which also relies on PFC activity. Lastly in male rhesus during adolescence in both humans and rats. The evidence for the macaques, pre-pubertal gonadectomy was associated with in- role of pubertal onset in the maturation of the functions of the creases in pre-pulse inhibition responses (Morris et al., 2010), cortex is less definitive, given the paucity of studies done where which is dependent on integrated cortical activity including the puberty was used as an experimental variable. Still, many types of PFC. behavior are influenced by gonadal steroids throughout life, sug- In rats, it has been widely found that steroid hormones in both gesting that puberty could affect neural reorganization as well as males and females contribute to performance on learning and the onset of hormonal modulation of behavior. Because these are

Please cite this article as: Juraska, J.M., Willing, J., Pubertal onset as a critical transition for neural development and cognition. Brain Research (2016), http://dx.doi.org/10.1016/j.brainres.2016.04.012i J.M. Juraska, J. Willing / Brain Research ∎ (∎∎∎∎) ∎∎∎–∎∎∎ 7 not easily separable in humans, we suggest more work in rodents through early adulthood. Proc. Natl. Acad. Sci. 101 (21), 8174–8179. is needed to investigate the effects of pubertal onset on the de- González, M., Cabrera-Socorro, A., Pérez-García, C.G., Fraser, J.D., López, F.J., Alonso, R., Meyer, G., 2007. Distribution patterns of estrogen receptor alpha and beta in velopment of higher order behavioral functioning. the human cortex and hippocampus during development and adulthood. J. Comp. Neurol. 503 (6), 790–802. Hammerslag, L.R., Gulley, J.M., 2014. Age and sex differences in reward behavior in adolescent and adult rats. Dev. Psychobiol. 56 (4), 611–621. 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