Doctor of Philosophy, Rockefeller University (2007)
Bachelor of Arts, Harvard University (2002)
Doctor of Medicine, Cornell University (2008)
Karl Deisseroth, Postdoctoral Faculty Sponsor
Excessive glucocorticoid exposure during chronic stress causes synapse loss and learning impairment. Under normal physiological conditions, glucocorticoid activity oscillates in synchrony with the circadian rhythm. Whether and how endogenous glucocorticoid oscillations modulate synaptic plasticity and learning is unknown. Here we show that circadian glucocorticoid peaks promote postsynaptic dendritic spine formation in the mouse cortex after motor skill learning, whereas troughs are required for stabilizing newly formed spines that are important for long-term memory retention. Conversely, chronic and excessive exposure to glucocorticoids eliminates learning-associated new spines and disrupts previously acquired memories. Furthermore, we show that glucocorticoids promote rapid spine formation through a non-transcriptional mechanism by means of the LIM kinase-cofilin pathway and increase spine elimination through transcriptional mechanisms involving mineralocorticoid receptor activation. Together, these findings indicate that tightly regulated circadian glucocorticoid oscillations are important for learning-dependent synaptic formation and maintenance. They also delineate a new signaling mechanism underlying these effects.
View details for DOI 10.1038/nn.3387
View details for Web of Science ID 000319509600011
View details for PubMedID 23624512
Mouse models are useful for studying genes involved in behavior, but whether they are relevant to human behavior is unclear. Here, we identified parallel phenotypes in mice and humans resulting from a common single-nucleotide polymorphism in the brain-derived neurotrophic factor (BDNF) gene, which is involved in anxiety-related behavior. An inbred genetic knock-in mouse strain expressing the variant BDNF recapitulated the phenotypic effects of the human polymorphism. Both were impaired in extinguishing a conditioned fear response, which was paralleled by atypical frontoamygdala activity in humans. Thus, this variant BDNF allele may play a role in anxiety disorders showing impaired learning of cues that signal safety versus threat and in the efficacy of treatments that rely on extinction mechanisms, such as exposure therapy.
View details for DOI 10.1126/science.1181886
View details for Web of Science ID 000274408300061
View details for PubMedID 20075215
Many studies have linked the structure and function of frontostriatal circuitry to cognitive control deficits in attention deficit hyperactivity disorder (ADHD). Few studies have examined the role of white matter tracts between these structures or the extent to which white matter tract myelination and regularity correlate in family members with the disorder.Functional imaging maps from a go/nogo task were used to identify portions of the ventral prefrontal cortex and striatum involved in suppressing an inappropriate action (i.e., cognitive control) in 30 parent-child dyads (N=60), including 20 dyads (N=40) with ADHD and 10 dyads (N=20) without ADHD. An automated fiber-tracking algorithm was used to delineate white matter fibers adjacent to these functionally defined regions based on diffusion tensor images. Fractional anisotropy, an index of white matter tract myelination and regularity derived from diffusion tensor images, was calculated to characterize the associations between white matter tracts and function.Fractional anisotropy in right prefrontal fiber tracts correlated with both functional activity in the inferior frontal gyrus and caudate nucleus and performance of a go/nogo task in parent-child dyads with ADHD, even after controlling for age. Prefrontal fiber tract measures were tightly associated between ADHD parents and their children.Collectively, these findings support previous studies suggesting heritability of frontostriatal structures among individuals with ADHD and suggest disruption in frontostriatal white matter tracts as one possible pathway to the disorder.
View details for DOI 10.1176/appi.ajp.2007.06101754
View details for Web of Science ID 000250811200020
View details for PubMedID 17974939