Summary: In a novel study, researchers reveal a sensitive developmental phase during adolescence that significantly influences adult impulsivity, aggression, and dopamine function in mice.
This study highlights the implications of stimulant drug exposure during this period. The research sheds light on how such exposure can lead to harmful consequences in healthy individuals, yet potentially offer benefits to those with pathological dopamine dysfunction. It also draws attention to the need for careful risk/benefit evaluation for drug exposure prior to adulthood.
A sensitive developmental period during adolescence was identified, influencing adult impulsivity, aggression, and dopamine function in mice.
This period can be hijacked by stimulant drug exposure with potentially harmful implications for healthy individuals, but potentially beneficial effects for those with dopamine dysfunction.
The researchers assert the importance of understanding the biology underlying drug use in adolescents for clear risk/benefit evaluations.
Source: Columbia University
In a breakthrough finding researchers at Columbia University Irving Medical Center identified a sensitive developmental period during adolescence that impacts adult impulsivity, aggression, and dopamine function in mice.
As organisms grow from embryo to adult, they pass through sensitive time periods where developmental trajectories are influenced by environmental factors. These windows of plasticity often allow organisms to adapt to their surroundings through evolutionarily selected mechanisms.
The new findings, published online today in the journal Molecular Psychiatry, indicate that stimulant drug exposure highjacks this period with potentially harmful consequences to healthy kids but also beneficial ones to kids with pathological dopamine hypofunction.
The dopamine system is pivotal in modulating and shaping adolescent behaviors.Dopamine system dysfunction is commonly implicated in adolescent-onset neuropsychiatric disorders, such as attention deficit disorders, depression disorders, and schizophrenia.
“First, we found that dopamine transporter blockade in mice during their mid-adolescence from postnatal day 32 to 41, but not before or after, increases adult aggression, impulsivity and the behavioral response to amphetamine in mice.
“We then found that dopaminergic neurons are also more active in these animals,” said Darshini Mahadevia, Ph.D., a research scientist at Columbia University Irving Medical Center (CUIMC), who co-led the study along with Deepika Suri, Ph.D. and Giulia Zanni, Ph.D., also research scientists at CUIMC.
To test for a causal relationship between altered neuronal activities and behavior, the researchers next applied modern genetic tools to artificially stimulate dopaminergic neurons during behavioral tasks that measure impulsivity.
In one such task, mice are trained to press a lever to receive a reward. Once mice become proficient at the task, they have to learn a new rule—withholding from pressing the lever to get rewarded. Mice that had their dopamine transporters blocked during mid-adolescence and mice that have their dopamine neurons artificially stimulated both perform badly on withholding from lever-pressing for rewards.
In another impulsivity task, mice are given the choice between a small immediate reward and a large later reward, the mouse version of the marshmallow test in humans, both assessing delay discounting.
“Again, the pharmacologic as well as the direct neuronal manipulation both increase impulsive behavior, making mice choose the immediate small rewards over the large later rewards,” said Dr. Suri.
While the investigation of sensitive periods in brain development has a long history, it has largely been focused on sensory systems. As an early recognition for the significance of this fundamental process, Hubel and Wiesel received the Nobel Prize in Physiology and Medicine (1981) for their work on ocular dominance plasticity in the 1960s.
“Studying sensitive developmental periods that impact complex behaviors, such as impulsivity and aggression, is novel and will aid in understanding the origins of psychiatric disorders, as well as their diagnosis, prevention, and treatment,” said Dr. Zanni.
“By identifying these ‘negative’ consequences of adolescent dopamine transporter blockade on brain development and behavior in mice, we are tempted to speculate that adolescent stimulant exposure in humans will likewise increase aggression, impulsivity, and potential susceptibility to drug addiction later in life.”
The researchers said that because the experiments were performed in wild-type animals, the findings cannot directly translate to the clinically appropriate use of psychostimulants (for example to treat attention deficit disorders), but perhaps more so to chronic recreational use or improper prescription.
In a diseased state that results from dopamine system hypofunction, transient exposure to psychostimulants during adolescence might potentially be corrective, but this hypothesis needs to be experimentally tested.
“Critically, we argue that an understanding of the underlying biology is necessary for a clear risk/benefit evaluation of recreational or therapeutic drug exposure prior to adulthood” said Dr. Ansorge, the senior author of the study.
About this neurodevelopment and neuroscience research news
Dopamine transporter blockade during adolescence increases adult dopamine function, impulsivity, and aggression
Sensitive developmental periods shape neural circuits and enable adaptation. However, they also engender vulnerability to factors that can perturb developmental trajectories. An understanding of sensitive period phenomena and mechanisms separate from sensory system development is still lacking, yet critical to understanding disease etiology and risk.
The dopamine system is pivotal in controlling and shaping adolescent behaviors, and it undergoes heightened plasticity during that time, such that interference with dopamine signaling can have long-lasting behavioral consequences.
Here we sought to gain mechanistic insight into this dopamine-sensitive period and its impact on behavior. In mice, dopamine transporter (DAT) blockade from postnatal (P) day 22 to 41 increases aggression and sensitivity to amphetamine (AMPH) behavioral stimulation in adulthood.
Here, we refined this sensitive window to P32-41 and identified increased firing of dopaminergic neurons in vitro and in vivo as a neural correlate to altered adult behavior. Aggression can result from enhanced impulsivity and cognitive dysfunction, and dopamine regulates working memory and motivated behavior. Hence, we assessed these behavioral domains and found that P32-41 DAT blockade increases impulsivity but has no effect on cognition, working memory, or motivation in adulthood.
Lastly, using optogenetics to drive dopamine neurons, we find that increased VTA but not SNc dopaminergic activity mimics the increase in impulsive behavior in the Go/NoGo task observed after adolescent DAT blockade.
Together our data provide insight into the developmental origins of aggression and impulsivity that may ultimately improve diagnosis, prevention, and treatment strategies for related neuropsychiatric disorders.