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Schaid, M. D.

Publications and source records attributed to Schaid, M. D..

5 recordsLinked to original sources

Region-specific Nucleus Accumbens Dopamine Signals Encode Distinct Aspects of Avoidance Learning

Avoidance learning - learning to avoid bad outcomes - is an essential survival behavior. Dopamine signals are widely observed in response to aversive stimuli, indicating they could play a role in learning about how to avoid these stimuli. However, it is unclear what computations dopamine signals perform to support avoidance learning. Furthermore, substantial heterogeneity in dopamine responses to aversive stimuli has been observed across nucleus accumbens (NAc) subregions. To understand how heterogeneous dopamine responses to aversive stimuli contribute to avoidance learning, we recorded NAc core (Core) and NAc ventromedial shell (vmShell) dopamine during a task in which mice could avoid a footshock punishment by moving to the opposite side of a 2-chamber apparatus during a five-second warning cue. We found that NAc Core and vmShell dopamine signals responded oppositely during shocks and warning cues. Both signals evolved substantially - but differently - with learning. NAc vmShell dopamine responses to cues and shocks were present during early learning but not sustained during expert performance. NAc Core dopamine responses strengthen with learning and are especially evident during expert performance. Our data support a model in which NAc vmShell dopamine guides initial cue-shock associations by signaling salience, while NAc Core dopamine encodes prediction errors that guide the consolidation of avoidance learning.

neuroscience↗

Chronically elevated corticosterone impairsdopaminergic transmission in the dorsomedialstriatum by sex-divergent mechanisms

BackgroundMajor depressive disorder (MDD) is a leading cause of disability worldwide. Individuals with MDD exhibit decreased motivation and deficits in reward processing along with chronically elevated levels of the stress hormone, cortisol. However, the mechanistic relationship between chronically elevated cortisol and behavioral deficits in motivation and reward processing remains unclear. Given that women are diagnosed with MDD at twice the rate of men, it is important to understand whether the mechanisms linking chronically elevated cortisol to the symptoms of MDD differ by sex. MethodsWe used subcutaneous implants to chronically elevate free plasma corticosterone (rodent homolog of cortisol; CORT) in male and female mice and examined changes in behavior and dopamine system function. We used operant training to assay reward-guided motivation and high-performance liquid chromatography to quantify striatal dopamine content. We assessed dopamine transporter (DAT) function using ex vivo slice imaging and in vivo fiber photometry in combination with a fluorescent dopamine sensor, dLight1.3b. We further quantified DAT expression and phosphorylation using western blot. ResultsWe found that chronic CORT treatment impaired reward-seeking in both sexes. In female but not male mice, CORT treatment reduced dopamine content in the dorsomedial striatum (DMS). In male but not female mice, the function of the dopamine transporter (DAT) was impaired in DMS. ConclusionsChronic elevation of CORT impairs reward-seeking by impairing dopaminergic transmission in the DMS, but via different mechanisms in male and female mice. A better understanding of these sex-specific mechanisms could lead to new directions in MDD diagnosis and treatment.

neuroscience↗

GuPPy, a Python toolbox for the analysis of fiber photometry data

Fiber photometry (FP) is an adaptable method for recording in vivo neural activity in freely behaving animals. It has become a popular tool in neuroscience due to its ease of use, low cost, the ability to combine FP with freely moving behavior, among other advantages. However, analysis of FP data can be a challenge for new users, especially those with a limited programming background. Here, we present Guided Photometry Analysis in Python (GuPPy), a free and open-source FP analysis tool. GuPPy is provided as a Jupyter notebook, a well-commented interactive development environment (IDE) designed to operate across platforms. GuPPy presents the user with a set of graphic user interfaces (GUIs) to load data and provide input parameters. Graphs produced by GuPPy can be exported into various image formats for integration into scientific figures. As an open-source tool, GuPPy can be modified by users with knowledge of Python to fit their specific needs.

neuroscience↗

Independent mechanisms underlie the protective effect of dietary polyunsaturated fatty acid supplementation and G&alphaz deficiency on the early type 1 diabetes phenotype of Non-obese diabetic (NOD) mice

Non-obese diabetic (NOD) mice deficient in Gz alpha subunit (Gz) are protected from developing hyperglycemia, even with early islet insulitis similar to wild-type mice. Similarly, wild-type (WT) NOD mice are protected from glucose intolerance when fed a diet enriched in eicosapentaneoic acid (EPA). In the beta-cell, Prostaglandin EP3 receptor (EP3), whose primary endogenous ligand is the arachidonic acid (AA) metabolite, prostaglandin E2, is specifically coupled to Gz. In this work, we tested whether dietary EPA supplementation, thereby reducing systemic PGE2 levels, would complement Gz loss in the NOD mouse model. WT and Gz-null NOD mice were fed an AA-enriched diet, EPA-enriched diet, or control diet upon weaning. After 12 weeks of diet feeding, glucose tolerance tests were performed and pancreatic islets and whole pancreas collected for ex vivo analyses, with the longer-term effect of an EPA-enriched diet on splenic T-cell populations quantified via flow cytometry. Our results reveal a polyunsaturated fatty acid-enriched diet, whether AA or EPA, improves wild-type NOD glucose tolerance by the same magnitude as Gz loss, but through almost completely different physiological and cellular mechanisms. Our results shed critical light on future research into novel pharmacological and dietary adjuvant therapies for T1D.

physiology↗

The protection of Gαz-null NOD mice from hyperglycemia is sexually dimorphic and only partially β-cell autonomous

The mechanisms that underlie the {beta}-cell pathophysiology of Type 1 Diabetes (T1D) are not fully understood. Our group has defined the unique heterotrimeric G protein alpha-subunit, Gz, as a key negative regulator of {beta}-cell signal transduction pathways. Non-obese diabetic (NOD) mice lacking Gz throughout the body are protected from developing T1D-like hyperglycemia. To determine whether this phenotype is {beta}-cell autonomous, we generated and validated a {beta}-cell-specific Gz knockout ({beta}KO) on the NOD background and characterized the phenotype of female and male cohorts. Long-term hyperglycemia incidence was lower in Gz {beta}KO mice as compared to wild-type (WT) controls, but, unlike global Gz knockout mice, this protection was incomplete. While young male and female Gz {beta}KO NOD mice had improved glucose tolerance, WT NOD males were significantly less glucose tolerant than females, and only female Gz {beta}KO mice retained improved glucose tolerance at 28-29 weeks of age. Conversely, {beta}-cell-specific Gz loss only influenced insulitis in 28-29-week old male NOD mice, a phenotype correlating directly with body burden of glucose during oral glucose challenge. Using surrogates for {beta}-cell function and apoptosis, the partial penetrance of euglycemia in Gz {beta}KO NOD was best explained by an early failure to up-regulate {beta}-cell proliferation. We conclude {beta}-cell Gz is an important regulator of the sexually-dimorphic T1D-like phenotype of NOD mice. Yet, other factors must be important in imparting full protection from the disease.

physiology↗