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), https://doi.org/10.1016/j.psyneuen.2017.08.009

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.

Faculty Forum: Characterizing Effects of Inequality on Brain Development & Strengthening Resilience against Adversity

UC Berkeley’s Vice Chancellor for Research is holding a faculty forum on Characterizing Effects of Inequality on Brain Development & Strengthening Resilience against Adversity on Tuesday, October 4th at the Faculty Club.  The event is convened by Linda Wilbrecht, Silvia Bunge, Daniela Kaufer, Julianna Deardorff, and Lance Kriegsfeld
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October 2nd, 2016|Tags: |

Wilbrecht in Conversation with Tom Stoppard and Carey Perloff

On Monday, October 3rd, Linda Wilbrecht will join Tom Stoppard and Carey Perloff in conversation at the ACT Theater.

Tom Stoppard and Carey Perloff—In Conversation

Monday, October 3, 7 p.m.
A.C.T.’s Geary Theater

Tony, Academy, and Olivier Award winner Tom Stoppard will join A.C.T. Artistic Director Carey Perloff “In Conversation” at The Geary Theater where they will discuss their decades-long collaboration and why Stoppard has long referred to A.C.T. as his “American home.” They will be joined on stage by neuroscientist Linda Wilbrecht from the University of California, Berkeley.

October 1st, 2016|Tags: |

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, http://dx.doi.org/10.1016/j.brainres.2016.08.042

Long-range orbitofrontal and amygdala axons show divergent patterns of maturation in the frontal cortex across adolescence

The adolescent transition from juvenile to adult is marked by anatomical and functional remodeling of brain networks. Currently, the cellular and synaptic level changes underlying the adolescent transition are only coarsely understood. Here, we use two-photon imaging to make time-lapse observations of long-range axons that innervate the frontal cortex in the living brain. We labeled cells in the orbitofrontal cortex (OFC) and basolateral amygdala (BLA) and imaged their axonal afferents to the dorsomedial prefrontal cortex (dmPFC). We also imaged the apical dendrites of dmPFC pyramidal neurons. Images were taken daily in separate cohorts of juvenile (P24–P28) and young adult mice (P64–P68), ages where we have previously discovered differences in dmPFC dependent decision-making. Dendritic spines were pruned across this peri-adolescent period, while BLA and OFC afferents followed alternate developmental trajectories. OFC boutons showed no decrease in density, but did show a decrease in daily bouton gain and loss with age. BLA axons showed an increase in both bouton density and daily bouton gain at the later age, suggesting a delayed window of enhanced plasticity. Our findings reveal projection specific maturation of synaptic structures within a single frontal region and suggest that stabilization is a more general characteristic of maturation than pruning.

Johnson CM, Loucks A, Peckler H, Thomas AW, Janak P, Wilbrecht L. (in press) Long-range orbitofrontal and amygdala axons show divergent patterns of maturation in the frontal cortex across adolescence. Developmental Cognitive Neuroscience (2016)

Rule learning enhances structural plasticity of long range axons in frontal cortex

Rules encompass cue-action-outcome associations used to guide decisions and strategies in a specific context. Subregions of the frontal cortex including the orbitofrontal cortex (OFC) and dorsomedial prefrontal cortex (dmPFC) are implicated in rule learning, although changes in structural connectivity underlying rule learning are poorly understood. We imaged OFC axonal projections to dmPFC during training in a multiple choice foraging task and used a reinforcement learning model to quantify explore–exploit strategy use and prediction error magnitude. Here we show that rule training, but not experience of reward alone, enhances OFC bouton plasticity. Baseline bouton density and gains during training correlate with rule exploitation, while bouton loss correlates with exploration and scales with the magnitude of experienced prediction errors. We conclude that rule learning sculpts frontal cortex interconnectivity and adjusts a thermostat for the explore–exploit balance.

Johnson C, Peckler H,Tai LH, Wilbrecht L., Rule learning enhances structural plasticity of long range axons in frontal cortex. Nature Communications (2016)

Rule learning enhances structural plasticity of long range axons in frontal cortex

Cell-Type-Specific Control of Brainstem Locomotor Circuits by Basal Ganglia

The basal ganglia (BG) are critical for adaptive motor control, but the circuit principles underlying their pathway-specific modulation of target regions are not well understood. Here, we dissect the mechanisms underlying BG direct and indirect pathway-mediated control of the mesencephalic locomotor region (MLR), a brainstem target of BG that is critical for locomotion. We optogenetically dissect the locomotor function of the three neurochemically distinct cell types within the MLR: glutamatergic, GABAergic, and cholinergic neurons. We find that the glutamatergic subpopulation encodes locomotor state and speed, is necessary and sufficient for locomotion, and is selectively innervated by BG. We further show activation and suppression, respectively, of MLR glutamatergic neurons by direct and indirect pathways, which is required for bidirectional control of locomotion by BG circuits. These findings provide a fundamental understanding of how BG can initiate or suppress a motor program through cell-type-specific regulation of neurons linked to specific actions.

Thomas K. Roseberry, A. Moses Lee, Arnaud L. Lalive, Linda Wilbrecht, Antonello Bonci, Anatol C. Kreitzer, Cell-Type-Specific Control of Brainstem Locomotor Circuits by Basal Ganglia, 64(3) Cell (Jan. 2016), http://www.cell.com/cell/abstract/S0092-8674%2815%2901701-8

Early maternal separation impacts cognitive flexibility at the age of first independence in mice

Early life adversity is associated with increased risk for mental and physical health problems, including substance abuse. Changes in neural development caused by early life insults could cause or complicate these conditions. Maternal separation (MS) is a model of early adversity for rodents. Clear effects of MS have been shown on behavioral flexibility in rats, but studies of effects of MS on cognition in mice have been mixed. We hypothesized that previous studies focused on adult mice may have overlooked a developmental transition point when juvenile mice exhibit greater flexibility in reversal learning. Here, using a 4-choice reversal learning task we find that early MS leads to decreased flexibility in post-weaning juvenile mice, but no significant effects in adults. In a further study of voluntary ethanol consumption, we found that adult mice that had experienced MS showed greater cumulative 20% ethanol consumption in an intermittent access paradigm compared to controls. Our data confirm that the MS paradigm can reduce cognitive flexibility in mice and may enhance risk for substance abuse. We discuss possible interpretations of these data as stress-related impairment or adaptive earlier maturation in response to an adverse environment.

A. Wren Thomas, Natalia Caporale, Claudia Wu, Linda Wilbrecht, Early maternal separation impacts cognitive flexibility at the age of first independence in mice, Developmental Cognitive Neuroscience, Available online 19 October 2015, ISSN 1878-9293, http://dx.doi.org/10.1016/j.dcn.2015.09.005.
(http://www.sciencedirect.com/science/article/pii/S187892931530030X)
Keywords: Development; Reversal; Prefrontal; Perseveration; Stress; Neglect