Neuroscience: Sex Hormones at Work in the Neocortex

Sex hormones have easy access to the brain and their receptors are expressed by cortical neurons. Until recently, little was known about what impact, if any, they have on cortical processing. New data reveal that estradiol potently alters inhibitory neurotransmission in the neocortex.

Kristen Delevich, David Piekarski, Linda Wilbrecht, Neuroscience: Sex Hormones at Work in the Neocortex,
29(4) Current Biology R122–R125 (2019) https://doi.org/10.1016/j.cub.2019.01.013, http://www.sciencedirect.com/science/article/pii/S0960982219300156

Neuroscience: Sex Hormones at Work in the Neocortex2019-02-22T15:49:13+00:00

Adolescence and “Late Blooming” Synapses of the Prefrontal Cortex

The maturation of the prefrontal cortex (PFC) during adolescence is thought to be important for cognitive and affective development and mental health risk. Whereas many summaries of adolescent development have focused on dendritic spine pruning and gray matter thinning in the PFC during adolescence, we highlight recent rodent data from our laboratory and others to call attention to continued synapse formation and plasticity in the adolescent period in specific cell types and circuits. In particular, we highlight changes in inhibitory neurotransmission onto intratelencephalic (IT-type) projecting cortical neurons and late expansion of connectivity between the amygdala and PFC and the ventral tegmental area and PFC. Continued work on these “late blooming” synapses in specific cell types and circuits, and their interrelationships, will illuminate new opportunities for understanding and shaping the biology of adolescent development. We also address which aspects of adolescent PFC development are dependent on pubertal processes.

Kristen Delevich, A. Wren Thomas, and Linda E. Wilbrecht, Adolescence and “Late Blooming” Synapses of the Prefrontal Cortex [local pdf], Cold Spring Harb Symp Quant Biol (2019)

Adolescence and “Late Blooming” Synapses of the Prefrontal Cortex2019-02-01T12:32:47+00:00

Mice engineered to mimic a common Val66Met polymorphism in the BDNF gene show greater sensitivity to reversal in environmental contingencies

A common human polymorphism in the gene that encodes brain derived neurotrophic factor (BDNF), Val66Met, is considered a marker of vulnerability for mental health issues and has been associated with cognitive impairment. An alternate framework has been proposed in which “risk alleles” are reinterpreted as “plasticity alleles” that confer vulnerability in adverse environments and positive effects in neutral or positive environments (Belsky et al., 2009). These frameworks produce divergent predictions for tests of learning and cognitive flexibility. Here, we examined multiple aspects of learning and cognitive flexibility in a relatively new BDNF Val66Met mouse model (BDNF Val68Met, Warnault et al., 2016), including multiple choice discrimination and reversal, go/no-go learning and reversal, and appetitive extinction learning. We found that mice homozygous for the Met allele show more efficient reversal learning in two different paradigms, but learn at rates comparable to Val homozygotes on the multiple choice discrimination task, a go/no-go task, and in appetitive extinction. Our results dissociate reversal performance from go/no-go learning and appetitive extinction and support the plasticity allele framework that suggests BDNF Met carriers are potentially more sensitive to changes in the environment.

Angela Vandenberg, Wan Chen Lin, Lung-Hao Tai, Dorit Ron, Linda Wilbrecht, Mice engineered to mimic a common Val66Met polymorphism in the BDNF gene show greater sensitivity to reversal in environmental contingencies, 34 Developmental Cognitive Neuroscience 34–41 (2018)

Mice engineered to mimic a common Val66Met polymorphism in the BDNF gene show greater sensitivity to reversal in environmental contingencies2019-02-02T21:38:12+00:00

Imaging Striatal Dopamine Release Using a Non-Genetically Encoded Near-Infrared Fluorescent Catecholamine Nanosensor

Neuromodulation plays a critical role in brain function in both health and disease. New optical tools, and their validation in biological tissues, are needed that can image neuromodulation with high spatial and temporal resolution, which will add an important new dimension of information to neuroscience research. Here, we demonstrate the use of a catecholamine nanosensor with fluorescent emission in the 1000-1300 nm near-infrared window to measure dopamine transmission in ex vivo brain slices. These near-infrared catecholamine nanosensors (nIRCats) represent a broader class of nanosensors that can be synthesized from non-covalent conjugation of single wall carbon nanotubes (SWNT) with single strand oligonucleotides. We show that nIRCats can be used to detect catecholamine efflux in brain tissue driven by both electrical stimulation or optogenetic stimulation. Spatial analysis of electrically-evoked signals revealed dynamic regions of interest approximately 2 microns in size in which transients scaled with simulation intensity. Optogenetic stimulation of dopaminergic terminals produced similar transients, whereas optogenetic stimulation of glutamatergic terminals showed no effect on nIRCat signal. Bath application of nomifensine prolonged nIRCat fluorescence signal, consistent with reuptake blockade of dopamine. We further show that the chemically synthetic molecular recognition elements of nIRCats permit measurement of dopamine dynamics in the presence of dopamine receptor agonists and antagonists. These nIRCat nanosensors may be advantageous for future use because i) they do not require virus delivery, gene delivery, or protein expression, ii) their near-infrared fluorescence facilitates imaging in optically scattering brain tissue and is compatible for use in conjunction with other optical neuroscience tool sets, iii) the broad availability of unique near-infrared colors have the potential for simultaneous detection of multiple neurochemical signals, and iv) they are compatible with pharmacology. Together, these data suggest nIRCats and other nanosensors of this class can serve as versatile new optical tools to report dynamics of extracellular neuromodulation in the brain.

Abraham G Beyene, Kristen Delevich, Jackson Travis Del Bonis ODonnell, David J Piekarski, Wan Chen Lin, A Wren Thomas, Sarah J Yang, Polina Kosillo, Darwin Yang, Linda Wilbrecht, Markita P Landry, Imaging Striatal Dopamine Release Using a Non-Genetically Encoded Near-Infrared Fluorescent Catecholamine Nanosensor, biorxiv preprint (2018)

Imaging Striatal Dopamine Release Using a Non-Genetically Encoded Near-Infrared Fluorescent Catecholamine Nanosensor2019-02-02T22:06:38+00:00

Your Twelve-Year-Old’s Brain Chapter in Think Tank

Professor Wilbrecht’s essay, Your Twelve-Year-Old Isn’t Just Sprouting New Hair but Is Also Forming (and Being Formed by) New Neural Connections, appears in Think Tank: Forty Neuroscientists Explore the Biological Roots of Human Experience (David J. Linden, ed. 2018).

Your Twelve-Year-Old’s Brain Chapter in Think Tank2019-02-01T12:33:18+00:00

Importance of investing in adolescence from a developmental science perspective

This review summarizes the case for investing in adolescence as a period of rapid growth, learning, adaptation, and formational neurobiological development. Adolescence is a dynamic maturational period during which young lives can pivot rapidly—in both negative and positive directions. Scientific progress in understanding adolescent development provides actionable insights into windows of opportunity during which policies can have a positive impact on developmental trajectories relating to health, education, and social and economic success. Given current global changes and challenges that affect adolescents, there is a compelling need to leverage these advances in developmental science to inform strategic investments in adolescent health.

Ronald E. Dahl, Nicholas B. Allen, Linda Wilbrecht & Ahna Ballonoff Suleiman, Importance of investing in adolescence from a developmental science perspective, Nature (v 554) pp. 441–450 (Feb. 2018), doi:10.1038/nature25770

Importance of investing in adolescence from a developmental science perspective2019-02-02T22:07:32+00:00

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

Age, sex, and gonadal hormones differently influence anxiety- and depression-related behavior during puberty in mice2017-08-16T12:12:57+00:00

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.

Ovarian Hormones Organize the Maturation of Inhibitory Neurotransmission in the Frontal Cortex at Puberty Onset in Female Mice2017-08-02T18:45:16+00:00

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
.

Faculty Forum: Characterizing Effects of Inequality on Brain Development & Strengthening Resilience against Adversity2016-10-02T12:51:22+00:00

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.

Wilbrecht in Conversation with Tom Stoppard and Carey Perloff2016-10-01T12:48:22+00:00