Neuroscientists have new insights into why previous experiences influence future behaviors. Experiments in mice reveal that personal history, especially stressful events, influences how the brain processes whether something is positive or negative. These calculations ultimately impact how motivated a rodent is to seek social interaction or other kinds of rewards.

In a first of its kind study, Tufts University School of Medicine researchers demonstrate that interfering with the neural circuits responsible for emotional decisions can increase or decrease socially avoidant behaviors in mice, regardless of whether they had enriched or adverse experiences as pups. The findings, appearing February 13 in the Journal of Neuroscience, suggest that antisocial behaviors associated with childhood neglect or related forms of abuse may result from dysfunctional dopamine signaling in the midbrain.

Many aspects of motivation involve dopamine, the neurotransmitter responsible for pleasurable feelings. When a mammal does something that enhances the chances of survival, such as eat a tasty meal or engage in sex, dopamine levels surge. In humans (and mice), positive social interactions are generally rewarded by a burst of activity in the ventral tegmental area—a pathway of dopamine-releasing neurons. It connects the basolateral amygdala, a clump of nerves in the midbrain where emotions are processed, to the prefrontal cortex, where the brain makes critical decisions surrounding emotion and motivation. 

“If people with early life stress are losing the ability to send information from parts of the brain that are needed for motivated behaviors, it made sense that we’d see less crosstalk between these two areas,” says first author Bradly Stone, who conducted the research as a Tufts postdoctoral scholar. “The result that turned our heads was that early life stress reduces the number of dopaminergic neurons between the ventral tegmental area and basolateral amygdala, suggesting that network architecture is impaired.”

To test this hypothesis, Stone and his colleagues leveraged cutting-edge laboratory techniques that allowed them to artificially activate or silence dopamine inputs into the basolateral amygdala from the ventral tegmental area. They applied this to a classic behavioral protocol in which a mouse is given the choice to investigate chambers with either a toy or a stranger mouse. Mice with carefree early days visited the stranger mouse as expected. However, mice that experienced maternal neglect primarily opted to do nothing or interact with the toy. This was only revealed when the investigators activated the dopaminergic neurons between the ventral tegmental area and basolateral amygdala. Importantly, when dopaminergic neurons were turned off in animals with carefree early days, they started behaving like animals who grew up with maternal neglect. 

“This experiment was a beautiful part to this story that really made me believe in the work,” says Stone. “It’s evidence that social avoidance is governed by a delicate balance of interconnected neural elements and early life stress shapes these connections in a nuanced way that impairs their ability to function.”

Shaping Emotions by Redirecting Brain Signals

The Journal of Neuroscience study is one of several elucidating the role of the basolateral amygdala in stress, reward, and psychiatric illness from the lab of Jamie Maguire, the Kenneth and JoAnn G Wellner Professor of Neuroscience at Tufts School of Medicine. 

Stone’s co-author Pantelis Antonoudiou, a senior scientist in the Maguire Lab, led a related project, appearing in the journal Cell Reports in July 2024, which explored the influence of previous experiences on information routing through the basolateral amygdala and the impact on mouse behavior. The team was particularly interested in which connections caused mice to either exhibit avoidance and helplessness related to living under conditions of chronic unpredictable stress or actively explore new stimuli, associated with inhabiting enriched environments. 

“We know the basolateral amygdala is an important hub for emotional processing and that certain projections have different effects on behaviors, but we wanted to learn how experiences, negative or positive, can modify those downstream circuits,” says Antonoudiou. “We saw that specific cell subpopulations of the basolateral amygdala are differentially activated or suppressed depending on previous experiences, biasing how information is processed.”

Part of what makes living things unique is the way they respond to encountering something new. Decisions to engage with an unknown member of the same species or avoid a potential food source can mean the difference between survival and death and are influenced by what’s felt “good” or “bad” throughout an individual’s life. Antonoudiou’s work pinpoints the mechanisms behind these events, finding that previous experiences shape the exchange of information from the basolateral amygdala to other parts of the brain.

The researchers observed that mice with chronic stress have increased crosstalk between the basolateral amygdala and the bed nucleus of the stria terminalis, implicated in the body’s stress response, and less connectivity with the nucleus accumbens, commonly associated with reinforcement learning. By artificially suppressing the former and stimulating the latter, Antonoudiou and colleagues saw reduced behavioral deficits in stressed mice, allowing them to function as if they grew up without those experiences.

Specialized Amygdala Cells Control Reward Seeking

“If you were to think of the lab as a wheel, we’re all spokes, and in the center would be the basolateral amygdala,” says Kenneth Amaya, one Maguire’s postdoctoral scholars. He recently conducted a series of animal experiments, published in the journal Current Biology in April 2024, investigating how neurons within the basolateral amygdala contribute to learning about the value of rewards. These specific cells, called parvalbumin interneurons, have been associated with regulating fearful behaviors, such as rodent freezing when a threat is detected, but new evidence shows they’re also involved in regulating reward.

“Fear and reward are two sides of the same “survival” coin, as they’re definitely at odds with one another, especially from an evolutionary perspective,” he says. “If you have two processes that are constantly competing for control, one of them is going to win—there are times when an animal needs to throw the fear aside and risk it all.” 

The research team first measured basolateral amygdala activity while mice consumed solutions from two bottles, one plain water and one made up of 20% sucrose, a sweet treat for rodents that quickly becomes the option they prefer. The researchers monitored neural activity in the basolateral amygdala and saw unique brain activity tied to the consumption of the sucrose solution. In their next experiment, they artificially stimulated parvalbumin interneurons in mice during plain water consumption, which mimicked the natural reward activity in the brain and drove the animals to prefer one water bottle over an identical water bottle. And if parvalbumin interneuron activity was suppressed, mice no longer displayed a preference. Amaya doesn’t believe that parvalbumin interneurons are essential for mice to feel rewards, but the cells are likely regulating an animal’s motivation for a reward.

Maguire is senior author on all three studies, which collectively build a case that the basolateral amygdala, whether making us feel fear or anxiety or calculating the value of a reward, is constantly looking out for our survival. The group is actively looking at how this biology lends itself to psychiatric illness and whether there are potential therapies that could support a healthy network and behavioral states.

“The Maguire Lab is a team of experts with different skill sets who have come together to do things that could never be done before,” says Stone. “The environment that Jamie has created fosters all lines of thinking,” adds Amaya. “Working here is like attending a conference every day.”