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Effects of Stress on Dopamine Circuit Structure and Function
A properly functioning dopamine system is vital for mental health. Stress is a powerful risk factor for psychiatric disorders such as depression and addiction. The Lerner Lab studies how stress impacts the development and function of the dopamine system.
We examine how stress during development – from early childhood to adolescence – changes how dopamine circuits form, connect, and process information. Altered dopamine circuit structures due to developmental stress can cause permanent changes to dopamine circuit function, which we probe using a suite of in vivo and ex vivo circuit interrogation tools.
The Lerner Lab also studies the molecular pathways that allow stress hormone signaling to impact dopamine circuit function in adulthood. We are particularly interested in how gonadal hormone signaling interacts with stress hormone signaling to produce differing effects of stress by sex.
An image of a single dye-filled dopamine neuron, which can be used for assessing the structure of neuronal processes and interrogating the location of incoming synapses via subcellular ChR2-assisted circuit mapping (sCRACM).
Modified rabies vectors can query whole-brain inputs to specific subsets of midbrain dopamine neurons.
Here, we observe that inputs to dopamine neurons from the striatum (labeled in green) arise from dopamine D1 receptor-expressing cells (red; above image). Changes to dopamine neuron inputs can occur due to stress.
Chronically dysregulated corticosterone impairs dopaminergic transmission in the dorsomedial striatum by sex-divergent mechanisms (Holloway et al., NPP, 2023).
Here, we investigated the mechanistic relationship between chronically dysregulated stress hormone signaling and behavioral deficits in motivation and reward processing. We found effects in male and female mice, but by sex-divergent mechanisms. In male but not female corticosterone (CORT)-treated mice, we observed impairments in dopamine transporter (DAT) function in the dorsomedial striatum (DMS). Using fiber photometry to monitor dopamine transmission (dLight1.3b), we saw that increases in dopamine release provoked by administration of a DAT inhibitor were blunted in CORT-treated male mice.
Hidden variables in stress neurobiology research (Holloway and Lerner, TINS, 2023).
In this opinion article, we discuss our philosophy for dissecting stress-induced behavioral changes across cognitive domains. We highlight key issues and suggest ways forward in stress neurobiology research that may improve the ability to assess stress mechanisms and translate preclinical findings.
