Rare human gene variant in ADHD, autism exposes fundamental sex differences: Study in mice uncovers surprising difference in male and female dopamine synapses supporting attention, movement, motivation and pleasure

The prevalence, age at onset, and clinical symptoms of virtually all neuropsychiatric disorders differ between men and women. Disorders with pronounced sexual bias include Attention Deficit Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD), in which the ratio of diagnosed males/females is approximately 4 to 1. Whether this skewed relationship is due to roles played in brain development, such as by sex-specific DNA sequences or hormones, or reflects how biological mechanisms and environmental influences induce different behavioral patterns in males and females remains an open area of ​​research.

Regardless of origin, altered behavior in these disorders signals a change in the functioning of key brain circuits that are wired during development, refined throughout life, and coordinated through the action of brain chemicals called neurotransmitters. A vital neurotransmitter that plays a key role in the behaviors altered by ADHD and ASD is dopamine, whose potent effects support motor initiation and coordination, motivation, reward, and social behavior, as well as attention and higher cognitive functioning. Although dopamine-sensitive circuits in the brain involved in these processes have been under scrutiny for decades and, in the case of ADHD, are the target of drugs like Adderall® and Ritalin®, the intrinsic sex-dependent differences in these signaling pathways could guide more precise ones Diagnoses and treatments have only recently become clear.

To better understand how dopamine levels are managed at brain synapses, neuroscientists at Florida Atlantic University, along with collaborators at the University of North Dakota School of Medicine and Health Sciences, have now added a significant piece to this puzzle by identifying key differences in the molecule Dopamine clearance machinery in the brains of male and female mice.

The new study, published in the journal Molecular Psychiatry and led by Randy Blakely, Ph.D., Professor of Biomedical Sciences at FAU’s Schmidt College of Medicine and Executive Director of FAU’s Stiles-Nicholson Brain Institute, offers new insights into how gender determines the mechanisms by which different Synapses monitor and regulate dopamine signaling. In addition, the impact of the described sex differences is particularly pronounced when the mice express a human genetic variant found in boys with either ADHD or ASD.

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“Because of the assumption that variations in sex hormones obscure data interpretation and that using one sex halves animal use and costs without losing important insights, many researchers who use animal models to study brain diseases work primarily with men . even more useful when modeling disorders that exhibit male biases,” Blakely said.

In a previous study looking for genetic changes in dopamine-regulating genes in children with ADHD, Blakely and his team identified a gene variant that alters the function of the dopamine transporter (DAT) in a unique way. Normally, DAT serves to remove dopamine from synapses by acting like a nanoscale dopamine vacuum cleaner. However, when the DAT variant was expressed in cells, it “walked backwards” and spat out dopamine instead of efficiently removing it. After generating the variant into the genome of mice, Blakely’s team found changes in behavior and drug response predicted by this aberrant DAT behavior, with a focus on traits associated with signaling pathways related to motor activation, habitual behavior, and associated with impulsivity. Remarkably, these studies were conducted exclusively with male mutant mice.

Blakely and Adele Stewart, Ph.D., first author of the report, Research Assistant Professor of Biomedicine at FAU’s Schmidt College of Medicine and member of FAU’s Stiles-Nicholson Brain Institute, recognized that more needs to be done, specifically in terms of how women would handle the mutation. Would the DAT mutation affect the same brain regions and behaviors in women as it does in men? The answer is a clear no. Females show effects of the mutation in brain regions unaffected in males and vice versa. Further work showed that this switch is due to a circuit switch in which brain pathways in males and females use a key DAT regulatory protein to increase the transporter’s reverse activity.

The behavioral consequences of this region-specific, sex-specific pattern of DAT regulation are profound, with the mutant DAT altering behavior in a pattern unique to each sex. For example, compared to wild-type females, mutant females appeared more fearful and had trouble recognizing novelty. Males, on the other hand, are less social and show increased persistent behavior, changes not seen in females.

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“Our work clearly shows that the female DAT mutant mice are not ‘protected’ from the effects of the mutation, but rather exhibit a unique set of behavioral changes associated with an ingrained, sex-specific architecture of the dopamine system,” Stewart said. “The same variant was also found in two unrelated boys with ASD, a disorder that often also presents with comorbid ADHD.”

Interestingly, the only reported clinical occurrence of the DAT variant in a woman was with a diagnosis of bipolar disorder (BPD). Both the mania and depression associated with BPD have been suggested to be linked to altered dopamine signaling. Blakely’s group have also reported high impulsivity traits in a female carrier of the same mutation examined in this latest article, suggesting that an overlap of dopamine-related traits may also occur between sexes, or perhaps the forms of impulsivity (eg e.g. wait versus action). be involved.

A “resilience” framework is often used to explain discrepancies in gender bias observed in neuropsychiatric disorders. However, recent evidence suggests that gender bias may be due, at least in part, to differences in symptomatology and associated comorbidities and the consequent failure of current diagnostic tools to ensure identification of the same disorder in both sexes.

“Although we understand that there are biological differences between rodent and human brains, studies like ours provide an important opportunity to explore biological mechanisms that contribute to sex differences in risk of neuropsychiatric disorders,” Stewart said. “What our study shows is that behavioral generalizations across genders can limit the diagnosis of mental illness, particularly when one gender converts changes into external signs, such as hyperactivity and aggression, as opposed to more internal manifestations, such as learning, memory, and mood, even if.” it’s the same molecule pathology is at work. Furthermore, our work supports the idea that treatment strategies should consider the sex-dependency of neural signaling mechanisms, rather than assuming that what’s good for the goose is also good for the gander. In fact, such therapies can either be not good for the gander at all, or good for an entirely different type of disorder.”

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The research provides a clear example of how genetic changes can have sex-dependent effects on physiology and behavior, depending on whether other co-regulatory genes are naturally expressed by the same cells.

“Because the basis for the differential response to the DAT mutation is the presence or absence of DAT regulation in these two domains, the implications are not unique to the few individuals with the genetic variant, nor are they limited to ADHD and ASD.” said Blakely. “Scientists studying other disorders related to altered dopamine signaling should consider whether the mechanism we have uncovered could influence sex-dependent characteristics of these diseases. As an extension, we now need to consider whether the mechanism we have discovered contributes to sex-dependent pathways in which dopamine signaling drives normal behavior.”

Co-authors of the study from the Department of Biomedical Science at FAU are Felix P. Mayer, Ph.D.; Raajaram Gowrishankar, Ph.D.; Gwynne L. Davis, Ph.D.; Lorena B. Areal, Ph.D.; Paul J. Gresch, Ph.D.; Rania M. Katamish; Samantha E. Stilley; Keeley Spit; Maximilian J. Rabil; and Maureen K Hahn, Ph.D. Also involved were Rodeania Peart and Faakhira A. Diljohn from FAU’s Harriet L. Wilkes Honors College, and Roxanne A. Vaughan, Ph.D., University of North Dakota School of Medicine and Health Sciences.

The study was supported by the Postdoctoral Training Program in Functional Neurogenomics (MH065215) and the BBRF’s NARSAD Young Investigator Grant to Stewart; a Max Kade fellowship for Mayer and an NIH PhD fellowship (MH107132) for Davis; an NIH grant (2P20GM104360) to Vaughan; and an NIH grant (MH086530) awarded to Blakely. Peart and Wiggins received grants from the Office for Undergraduate Research and Inquiry at FAU.

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