Age, sex, and gonadal hormones differently influence anxiety- and depression-related behavior during puberty in mice

Anxiety and depression symptoms increase dramatically during adolescence, with girls showing a steeper increase than boys after puberty onset. The timing of the onset of this sex bias led us to hypothesize that ovarian hormones contribute to depression and anxiety during puberty. In humans, it is difficult to disentangle direct effects of gonadal hormones from social and environmental factors that interact with pubertal development to influence mental health. To test the role of gonadal hormones in anxiety- and depression-related behavior during puberty, we manipulated gonadal hormones in mice while controlling social and environmental factors. Similar to humans, we find that mice show an increase in depression-related behavior from pre-pubertal to late-pubertal ages, but this increase is not dependent on gonadal hormones and does not differ between sexes. Anxiety-related behavior, however, is more complex at puberty, with differences that depend on sex, age, behavioral test, and hormonal status. Briefly, males castrated before puberty show greater anxiety-related behavior during late puberty compared to intact males, while pubertal females are unaffected by ovariectomy or hormone injections in all assays except the marble burying test. Despite this sex-specific effect of pubertal hormones on anxiety-related behavior, we find no sex differences in intact young adults, suggesting that males and females use separate mechanisms to converge on a similar behavioral phenotype. Our results are consistent with anxiolytic effects of testicular hormones during puberty in males but are not consistent with a causal role for ovarian hormones in increasing anxiety- and depression-related behavior during puberty in females.

Josiah R. Boivin, David J. Piekarski, Jessica K. Wahlberg, Linda Wilbrecht, Age, sex, and gonadal hormones differently influence anxiety- and depression-related behavior during puberty in mice, Psychoneuroendocrinology (available online 12 August 2017),

Ovarian Hormones Organize the Maturation of Inhibitory Neurotransmission in the Frontal Cortex at Puberty Onset in Female Mice

The frontal cortex matures late in development, showing dramatic changes after puberty onset, yet few experiments have directly tested the role of pubertal hormones in cortical maturation. One mechanism thought to play a primary role in regulating the maturation of the neocortex is an increase in inhibitory neurotransmission, which alters the balance of excitation and inhibition. We hypothesized that pubertal hormones could regulate maturation of the frontal cortex by this mechanism. Here, we report that manipulations of gonadal hormones do significantly alter the maturation of inhibitory neurotransmission in the cingulate region of the mouse medial frontal cortex, an associative region that matures during the pubertal transition and is implicated in decision making, learning, and psychopathology. We find that inhibitory neurotransmission, but not excitatory neurotransmission, increases onto cingulate pyramidal neurons during peri-pubertal development and that this increase can be blocked by pre-pubertal, but not post-pubertal, gonadectomy. We next used pre-pubertal hormone treatment to model early puberty onset, a phenomenon increasingly observed in girls living in developed nations. We find that pre-pubertal hormone treatment drives an early increase in inhibitory neurotransmission in the frontal cortex, but not the somatosensory cortex, suggesting that earlier puberty can advance cortical maturation in a regionally specific manner. Pre-pubertal hormone treatment also accelerates maturation of tonic inhibition and performance in a frontal-cortex-dependent reversal-learning task. These data provide rare evidence of enduring, organizational effects of ovarian hormones at puberty and provide a potential mechanism by which gonadal hormones could regulate the maturation of the associative neocortex.

David J. Piekarski, Josiah R. Boivin, Linda Wilbrecht, Ovarian Hormones Organize the Maturation of Inhibitory Neurotransmission in the Frontal Cortex at Puberty Onset in Female Mice, 27(12) Current Biology p1735–1745.e3, June 19, 2017.

Does puberty mark a transition in sensitive periods for plasticity in the associative neocortex?

Postnatal brain development is studded with sensitive periods during which experience dependent plasticity is enhanced. This enables rapid learning from environmental inputs and reorganization of cortical circuits that matches behavior with environmental contingencies. Significant headway has been achieved in characterizing and understanding sensitive period biology in primary sensory cortices, but relatively little is known about sensitive period biology in associative neocortex. One possible mediator is the onset of puberty, which marks the transition to adolescence, when animals shift their behavior toward gaining independence and exploring their social world. Puberty onset correlates with reduced behavioral plasticity in some domains and enhanced plasticity in others, and therefore may drive the transition from juvenile to adolescent brain function. Pubertal onset is also occurring earlier in developed nations, particularly in unserved populations, and earlier puberty is associated with vulnerability for substance use, depression and anxiety. In the present article we review the evidence that supports a causal role for puberty in developmental changes in the function and neurobiology of the associative neocortex. We also propose a model for how pubertal hormones may regulate sensitive period plasticity in associative neocortex. We conclude that the evidence suggests puberty onset may play a causal role in some aspects of associative neocortical development, but that further research that manipulates puberty and measures gonadal hormones is required. We argue that further work of this kind is urgently needed to determine how earlier puberty may negatively impact human health and learning potential.

David J. Piekarski, Carolyn Johnson, Josiah R. Boivin, A. Wren Thomas, Wan Chen Lin, Kristen Delevich, Ezequiel Galarce and Linda Wilbrecht, Does puberty mark a transition in sensitive periods for plasticity in the associative neocortex?, Brain Research,

Brief cognitive training interventions in young adulthood promote long-term resilience to drug-seeking behavior

Environmental stress and deprivation increase vulnerability to substance use disorders in humans and promote drug-seeking behavior in animal models. In contrast, experiences of mastery and stability may shape neural circuitry in ways that build resilience to future challenges. Cognitive training offers a potential intervention for reducing vulnerability in the face of environmental stress or deprivation. Here, we test the hypothesis that brief cognitive training can promote long-term resilience to one measure of drug-seeking behavior, cocaine conditioned place preference (CPP), in mice. In young adulthood, mice underwent cognitive training, received rewards while exploring a training arena (i.e. yoked control), or remained in their home cages. Beginning 4 weeks after cessation of training, we conditioned mice in a CPP paradigm and then tested them weekly for CPP maintenance or daily for CPP extinction. We found that a brief 9-day cognitive training protocol reduced maintenance of cocaine CPP when compared to standard housed and yoked conditions. This beneficial effect persisted long after cessation of the training, as mice remained in their home cages for 4 weeks between training and cocaine exposure. When mice were tested for CPP on a daily extinction schedule, we found that all trained and yoked groups that left their home cages to receive rewards in a training arena showed significant extinction of CPP, while mice kept in standard housing for the same period did not extinguish CPP. These data suggest that in early adulthood, deprivation may confer vulnerability to drug-seeking behavior and that brief interventions may promote long-term resilience.

Josiah Boivin, Denise Piscopo, Linda Wilbrecht, Brief cognitive training interventions in young adulthood promote long-term resilience to drug-seeking behavior. Neuropharmacology