Page 14 - Abacoa Community News - November '22

Page 14, Abacoa

FAU Features from page 11 Psychiatry and led by Randy Blakely, Ph.D., professor of suggesting that overlap of traits linked to dopamine can also
Rare Human Gene Variant In biomedical science in FAU’s Schmidt College of Medicine and occur between the sexes, or perhaps the forms of impulsivity
executive director of the FAU Stiles-Nicholson Brain Institute,
(e.g. waiting versus action) may be involved.
A “resilience” framework often is used to explain
ADHD, Autism Exposes Vital provides new insight into how sex determines the mechanisms discrepancies in the sex bias observed in neuropsychiatric
by which distinct synapses monitor and regulate dopamine
Sex Differences signaling. Moreover, the impact the sex differences described is disorders. However, recent evidence suggests that sex bias can
particularly pronounced when the mice express a human genetic be due, at least in part, to differences in symptomology and
By Gisele Galoustian variant found in boys with either ADHD or ASD. associated comorbidities and the resultant failure of current
The prevalence, age of “Often, due to assumptions that sex hormone variation diagnostic instruments to assure identification of the same
onset, and clinical symptoms will cloud data interpretations, and that use of one sex will disorder in both sexes.
for virtually all neuropsychiatric cut animal use and costs in half without a loss of key insights, “While we understand that there are biological differences
disorders differ between many researchers using animal models to study brain disorders between rodent and human brains, studies like ours provide
men and women. Among the work chiefly with males, even more reasonable when modeling an important opportunity to explore biological mechanisms
disorders with pronounced disorders that exhibit male bias,” said Blakely. that contribute to sex differences in risk for neuropsychiatric
sex bias are attention-deficit/ In a prior study, looking for genetic changes in dopamine diseases,” said Stewart. “What our study shows is that
hyperactivity disorder (ADHD) regulatory genes in children with ADHD, Blakely and his behavioral generalizations across the sexes may limit diagnosis
and autism spectrum disorder (ASD), where the ratio of males/ team identified a gene variant that alters the function of the of mental illness, particularly if one sex translates alterations
females diagnosed is approximately four to one. Whether this dopamine transporter (DAT) in a peculiar way. Normally DAT into outward signs such as hyperactivity and aggression versus
skewed ratio arises from roles played in brain development by acts to remove dopamine from synapses, acting like a nanoscale more internal manifestations such as learning, memory and
sex-specific DNA sequences or hormones or reflects the way dopamine vacuum cleaner. When the DAT variant was expressed mood, even when the same molecular pathology is at work.
that biological mechanisms and environmental influences elicit in cells, however, it “ran backward,” spitting out dopamine rather What is more, our work supports the idea that treatment
behavioral patterns differently in males and females, remains an than efficiently removing it. After engineering the variant into the strategies should be cognizant of the sex-dependence of
area of open investigation. genome of mice, Blakely’s team found changes in behavior and neuronal signaling mechanisms rather than assuming treatment
Regardless of origin, altered behavior in these disorders drug responses predicted by this anomalous DAT behavior, with that what is good for the goose is good for the gander. In fact,
signals a change in the function of key brain circuits wired up an emphasis on traits linked to pathways related to locomotor such therapies may either not be good for the gander at all, or
during development, refined throughout life, and coordinated activation, habitual behavior and impulsivity. Notably, these good for a completely different kind of disorder.”
through the actions of brain chemicals called neurotransmitters. studies were performed exclusively with male mutant mice. The research provides a clear example of how genetic
One vital neurotransmitter that plays a key role in the behaviors Blakely and Adele Stewart, Ph.D., first author on the report, changes can have sex-dependent effects on physiology and
altered by both ADHD and ASD is dopamine, whose powerful a research assistant professor of biomedical science in FAU’s behavior, depending on whether other co-regulatory genes are
actions support motor initiation and coordination, motivation, Schmidt College of Medicine and a member of the FAU Stiles- naturally expressed by the same cells.
reward and social behavior, as well as attention and higher Nicholson Brain Institute, recognized there was more to be “Because the basis for the differential response to the DAT
cognitive function. Although dopamine-sensitive brain circuits done, particularly with respect to how females would handle mutation is the presence or absence of DAT regulation in these
engaged in these processes have been under scrutiny for decades, the mutation. Would the DAT mutation impact the same brain two areas, the implications do not just apply to the few individuals
and in the case of ADHD, are the target of medications such as regions and behaviors in females as it had done in males? The with the genetic variant nor are limited to ADHD and ASD,” said
Adderall and Ritalin , the intrinsic sex-dependent differences answer is a resounding no. Females show effects of the mutation Blakely. “Investigators exploring other disorders linked to altered
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in these pathways that could guide more precise diagnoses and in brain regions unaffected in males and vice versa. Further work dopamine signaling should consider whether the mechanism
treatments have only recently begun to be elucidated. revealed that this switch is due to a circuit flip in how brain we have uncovered could drive sex-dependent features of these
To better understand how dopamine levels at brain pathways in males and females use a key DAT regulator protein diseases. By extension, we now need to consider whether the
synapses are managed, neuroscientists from Florida Atlantic to magnify the backwards activity of the transporter. mechanism we have uncovered contributes to sex-dependent
University, along with collaborators at the University of North The behavioral consequences of this region-specific, ways in which dopamine signaling drives normal behavior.”
Dakota School of Medicine and Health Sciences, have now sex-biased pattern of DAT regulation are profound, with the Study co-authors from FAU’s Department of Biomedical
added a significant piece to this puzzle by establishing key mutant DAT altering behaviors in a pattern unique to each sex. Science are Felix P. Mayer, Ph.D.; Raajaram Gowrishankar,
differences in the molecular dopamine disposal machinery in For example, mutant females appeared more anxious and had Ph.D.; Gwynne L. Davis, Ph.D.; Lorena B. Areal, Ph.D.; Paul
the brains of male and female mice. issues with novelty recognition compared to wildtype females. J. Gresch, Ph.D.; Rania M. Katamish; Samantha E. Stilley;
The new research published in the journal Molecular Males on the other hand are less social and display increased Keeley Spiess; Maximilian J. Rabil; and Maureen K. Hahn,
perseverative behavior, changes not seen in females. Ph.D. Also participating were Rodeania Peart and Faakhira A.
“Our work clearly shows that the female mutant DAT mice

It’s The Law! are not ‘protected’ from the impact of the mutation, but rather, Diljohn from FAU’s Harriet L. Wilkes Honors College as well
as Roxanne A. Vaughan, Ph.D., University of North Dakota
exhibit a unique set of behavioral changes linked to an ingrained,
School of Medicine and Health Sciences.
sex-biased architecture of the dopamine system,” said Stewart. The study was supported by the Postdoctoral Training
Did You Know That, In “The same variant also has been found in two unrelated boys Program in Functional Neurogenomics (MH065215)
with ASD, a disorder that often also displays comorbid ADHD.”
and NARSAD Young Investigator Grant from the BBRF
Florida … Interestingly, the only reported clinical occurrence of the awarded to Stewart; a Max Kade fellowship to Mayer and
DAT variant in a female involved a diagnosis of bipolar disorder an NIH predoctoral fellowship (MH107132) to Davis; an
By Adam S. Gumson, Esq. (BPD). Both the mania and depression associated with BPD NIH grant (2P20GM104360) awarded to Vaughan; and
A deed cannot waive have been suggested to be linked to altered dopamine signaling. an NIH grant (MH086530) awarded to Blakely. Peart and
the homestead rights of Blakely’s group also has reported high impulsivity traits in a Wiggins received grant support from FAU’s Office for
a spouse unless it contains female carrier of the same mutation studied in this latest paper, Undergraduate Research and Inquiry.
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