The ability to alter brain activity and behavior by injecting chemicals into the body or shining light into the brain seems like something out of a sci-fi movie. Imagine if scientists could use these tools at a specific time in one’s life to prevent or reverse brain dysfunction related to decision making and information processing? While they’re not there yet, scientists are paving the way to answer this question. 

In a recent study published in eLife, researchers at the University of Rochester discovered that by manipulating neuronal activity in adolescent mice with impaired dopamine function in a specific part of the brain, they could restore neuronal activity and reverse the behavioral problems in the animal models (1). The team identified a new potential neuronal circuit to target for treating these impairments during neurodevelopment. The results also suggest a critical time window for treatment to prevent long term prefrontal cortex dopamine dysfunction that is characteristic of neuropsychiatric diseases such as schizophrenia and substance-use disorders.

The prefrontal cortex’s main source of dopamine comes from dopamine neurons in the ventral tegmental area (VTA). These neurons are important for cognitive control, the ability to perform goal-directed behaviors (2). In neuropsychiatric disorders, these dopamine neurons often have abnormal activity.

“A lot of psychiatric disorders are treated with anti-psychotics which are based on a main target of those drugs — dopamine receptor antagonists — but those drugs can [only] relieve psychotic symptoms like hallucinations. It’s really challenging to improve the cognitive functions like working memory or executive functions [that] affect the patient’s daily life,” said Kuan Hong Wang, a neurodevelopmental neuroscientist at the University of Rochester and coauthor of this study. “So, our research interest is motivated by the clinical and human disease relevance, but we’re also just very fascinated by how cognitive functions, particularly those mediated by the frontal lobe of our brain, are achieved in these [dopamine] circuits.”

To model prefrontal cortex dopamine disruptions, the researchers used mice that either had a mutation in the activity-regulated cytoskeletal (Arc) or disrupted-in-schizophrenia 1 (Disc1) gene, which cause low dopamine levels and are important for synaptic function in the prefrontal cortex (3,4). These mutant mice performed poorly on spatial navigation and memory tasks compared to healthy controls. At an anatomical level, the prefrontal cortex projecting VTA dopamine neurons of these animals released lower levels of dopamine. 

Given that VTA dopamine neuron function is impaired in these models, the team investigated whether they could rescue these impairments by manipulating VTA dopamine activity. To do this, Wang and his team leveraged the use of two state-of-the-art methods to manipulate neuron activity: optogenetics and chemogenetics. Optogenetics uses light pulses to enact time-sensitive control of neuron activity while chemogenetics uses a designer drug, such as Clozapine N-oxide, to modify neuron activity for long periods of time (5). Wang and his team decided to use these two techniques in these Arc and Disc1 mutant mice specifically during adolescence because that is a peak period for neuronal plasticity, after which brains start to solidify neuronal connections that ultimately inform cognitive functions such as goal planning and impulse control (6,7).

The researchers found that stimulating VTA dopamine neurons restored behavior and neuronal activity in Arc and Disc1 mutant mice to control mice levels and that these improvements lasted well into adulthood. When these mutant mice received VTA dopamine stimulation during adulthood, improvements were not observed, signifying that the rescuing effects in these models were specific to adolescence. “The most challenging and also exciting part is our long-term rescue because we can do a relatively short intervention,” said Wang.

The most challenging and also exciting part is our long-term rescue because we can do a relatively short intervention. 
- Kuan Hong Wang, University of Rochester

“It’s an interesting paper. It’s using new techniques and addressing an older problem,” said Bita Moghaddam, a neuroscientist from Oregon Health and Science University who was not involved in the study. The old problem in question is regarding how dopamine signaling influences cognitive function. 

While these findings are promising, Moghaddam was concerned about whether stimulating VTA dopamine neurons and their inputs into the prefrontal cortex may be impacting other pathways. “The part that was somewhat surprising was that they didn't take into account that the same pathway also is involved in anxiety and stress,” said Moghaddam. “If you stimulate the same pathway, with chemogenetics or optogenetics, animals become very anxious. It would be nice, potentially, to look into some models of anxiety and stress to see if they can distinguish it to have more elaborate cognitive testing.” 

For future experiments, Wang and his team plan to go deeper into the molecular mechanisms that drive these dopamine dynamics, allowing them to address Moghaddam’s concerns about the involvement of other signaling systems and behaviors. The team also plans to explore how neural manipulation could rescue dopamine deficits in adulthood, not just adolescence.

“Although this paper showed that we can do adolescent manipulation intervention to rescue a genetic deficit, in real life it's not easy to convince people to do any intervention when the disease is at an early stage,” said Wang. “So, the question we're really interested in testing is whether there's a way that we can in the adult animals… reopen the plasticity and then allow the beneficial therapeutic manipulation to be reintroduced into the brain.”

References

1. Mastwal, S. et al. Adolescent neurostimulation of dopamine circuit reverses genetic deficits in frontal cortex function. eLife  12, RP87414 (2023).
2. Ott, T. & Nieder, A. Dopamine and Cognitive Control in Prefrontal Cortex. Trends Cogn Sci  23, 213–234 (2019).
3. Managò, F. et al. Genetic Disruption of Arc/Arg3.1 in Mice Causes Alterations in Dopamine and Neurobehavioral Phenotypes Related to Schizophrenia. Cell Reports  16, 2116–2128 (2016).
4. Niwa, M. et al. Knockdown of DISC1 by In Utero Gene Transfer Disturbs Postnatal Dopaminergic Maturation in the Frontal Cortex and Leads to Adult Behavioral Deficits. Neuron  65, 480–489 (2010).
5. Vlasov, K., Van Dort, C. J. & Solt, K. Chapter Eleven - Optogenetics and Chemogenetics. Methods Enzymol  603, 181–196 (2018).
6. Wahlstrom, D., Collins, P., White, T., & Luciana, M. Developmental changes in dopamine neurotransmission in adolescence: behavioral implications and issues in assessment. Brain and cognition  72, 146–159 (2010).
7. Selemon, L. D. A role for synaptic plasticity in the adolescent development of executive function. Transl Psychiatry  3, e238 (2013).