The Effect of Genetic Risk and Maternal Behavior on Children’s Amygdala Connectivity

Post by Shireen Parimoo

What's the science?

Depression and anxiety are internalizing disorders, which means that their symptoms are primarily experienced internally (e.g. sadness, loneliness) rather than being directed externally (e.g. impulsive behavior, bullying). Adverse childhood experiences like negative parental behavior are associated with a higher incidence of internalizing symptoms and depression later in life. Depression has also been linked to disrupted functioning of the amygdala and the hypothalamic-pituitary-adrenal (HPA) axis, a set of brain regions that control the body’s reaction to stress. Together, negative childhood experiences and having certain genes associated with the HPA axis are related to having depression, but the mechanism of this interaction is unclear. This week in NeuroImage, Pozzi and colleagues used functional magnetic resonance imaging (fMRI) to delineate the relationship between HPA genetic risk, parental behavior, amygdala activation, and children’s depressive symptoms.

How did they do it?

Eighty children aged 8 - 9 years old participated in a longitudinal study with two time points. At the first time point, the authors recorded interactions between the children and their mother and 18 months later, the children performed an emotional processing task while undergoing fMRI scanning. The mother-child interactions were each 15 minutes long and consisted of an event-planning interaction and a problem-solving interaction. The mothers’ behavior was categorized into negative (e.g. anger) and positive (e.g. listening) behavior during each interaction. Saliva samples were also collected at the first time point to assess genetic risk, yielding a composite HPA genetic risk score based on the number of HPA-related genes that they possessed.

At the second time point, children completed questionnaires assessing internalizing symptoms, depression, and anxiety, while their mothers completed questionnaires assessing maternal depression and their children’s internalizing symptoms. The children also completed an emotional face-matching task in which they had to match the gender of an angry or fearful target face with one of two other faces. In the control condition, participants matched shapes instead of faces. The authors first examined task-related activity in the amygdala when participants performed the face compared to the shape matching task. They then performed a generalized psychophysiological interaction (gPPI) analysis to determine how the connectivity between the amygdala and other regions of the brain were related to the interaction between genetic risk, child functioning, and maternal behavior.

What did they find?

There were no direct associations between amygdala activation during the emotional face-matching task, and the interaction between genetic risk, and maternal behavior. Genetic risk moderated the relationship between negative maternal behaviors and brain connectivity. Specifically, higher genetic risk was linked to greater amygdala connectivity with the right superior frontal gyrus when mothers exhibited more negative behaviors during the problem-solving task. Conversely, if mothers exhibited more negative behaviors but the child’s genetic risk was low, the connectivity between the amygdala and the right superior frontal gyrus was also lower. During the event planning task, negative maternal behavior was associated with greater connectivity between the amygdala and the postcentral gyrus in the presence of high genetic risk, but reduced amygdala connectivity with fronto-parietal regions when genetic risk was low. This suggests that how mothers interact with their children affects the children’s amygdala’s connectivity in different ways depending on the level of genetic risk for HPA axis dysregulation.

Finally, genetic risk was not directly associated with children’s internalizing or depressive symptoms. However, there was an indirect relationship between genetic risk and child functioning that was mediated by the amygdala’s connectivity to the precuneus. Higher genetic risk was linked to more internalizing symptoms in children via higher amygdala-precuneus connectivity.

What's the impact?

This study is the first to show that genetic risk influences the effect that negative maternal behavior has on brain activity (connectivity) related to children’s emotion processing. The results further illustrate that altered brain functioning underlies the interaction between genetic risk factors and depressive symptoms. These findings provide deeper insight into how genetic and environmental variables might contribute to the development of internalizing disorders such as depression and anxiety.

Pozzi et al. Interaction between hypothalamic-pituitary-adrenal axis genetic variation and maternal behavior in the prediction of amygdala connectivity in children. NeuroImage (2019). Access the original scientific publication here.

Creation and Recollection of Artificial Memories

Post by Deborah Joye

What's the science?

As animals move through the world, they learn to associate certain environmental cues with events which help them survive. These memory associations have been localized to specific brain regions and underlying circuits. Specifically, the way that mice create odor associations is well-characterized and occurs similarly across individuals. If our detailed understanding of odor memory in mice is correct, it leads to an interesting question: can a false memory be created through direct stimulation of the brain? And can this memory be recalled by something in the real world, as if it actually happened? This week in Nature Neuroscience, Vetere and colleagues use association training along with direct cell-type- and region-specific brain stimulation to demonstrate that both good and bad artificial memory associations can be created in mice and recalled by a real-world cue.

How did they do it?

The authors first trained mice to form a real odor association by pairing a specific odor (acetophenone) with a mild foot shock. Since memory associations depend on presentation of the odor and the foot shock right after one another, the authors included conditions where the odor or the foot shock were presented independently or were presented 24 hours apart from one another (too far apart for memory associations to form). In the memory test, mice were put into a box with two chambers – one with the trained odor and the other with a new odor. The idea is that if a memory of the odor-foot shock pairing has been formed, the mouse will avoid the compartment containing the foot-shock-paired odor.

The authors then repeated this experimental structure multiple times. First, to test whether the odor association could be formed by direct brain stimulation, the authors genetically altered acetophenone-specific olfactory cells to be activated by a laser (called optogenetic stimulation). Mice were then exposed to the same two-chamber box containing either acetophenone or another smell. Second, to test that both the odor and the foot-shock could be created using only direct brain stimulation, the authors used optogenetics to activate both olfactory cells and cells in the brain associated with positive or negative experience (laterodorsal tegmental or lateral habenula inputs to the ventral tegmental area, respectively). Finally, since cells in the basolateral amygdala are important for memory associations, the authors tested whether this region is likewise necessary for artificial memory associations by chemogenetically silencing it. They virally expressed an inhibitory DREADD (designer receptor exclusively activated by designer drug) to turn off basolateral amygdala cells in the presence of a specific chemical. The authors then repeated the memory association experiment, using the inhibitory DREADD to block basolateral amygdala activity a subset of mice.

What did they find?

The authors found that mice formed memory associations between an odor and a foot-shock, as expected. Direct optogenetic stimulation of acetophenone-sensitive olfactory cells paired with foot shock also produced a memory association. This memory association could be recalled by mice, as evidenced by an avoidance of the compartment containing the actual acetophenone odor. Optogenetic stimulation of olfactory cells paired with stimulation of negative experience cells produced a behavioral aversion to the acetophenone odor, like mice that had been exposed to a real foot shock. In contrast, optogenetic stimulation of olfactory cells paired with stimulation of positive experience cells produced a behavioral attraction to the acetophenone odor. In all instances, artificial memory associations were only created if stimulation of the brain regions occurred close together in time, as with real memory associations. The authors also found that real and artificial memory associations engaged similar neural circuits, as shown by markers of cellular activation. Finally, when researchers chemogenetically blocked basolateral amygdala activity with DREADDs, expressions of both real and artificial memory associations were lost.

What's the impact?

This study successfully creates a fully artificial memory in mice through direct brain stimulation. The characteristics of this artificial memory were like a natural memory: time dependent, similar brain circuits, behavioral responses were specific to the trained cue, and memory expression depended on the basolateral amygdala. This is the first study to show that artificially created memories can be recalled by a real-world cue. This study presents a valuable window into how memory associations are created and integrated with real-world experience.

Vetere et al., Memory formation in the absence of experience, Nature Neuroscience (2019).Access the original scientific publication here.

Why We Make Decisions Together

Post by Anastasia Sares

What’s the science?

Collective decision-making behaviors have been demonstrated in social animals like bees, ants, and fish. Humans are also social creatures, and like these other species, we often make decisions together, even though we strongly value autonomy. What benefit is there in giving up some of our autonomy and making a decision as a part of a group? This week in Nature Human Behavior, El Zein and colleagues suggested that we decide together in order to dilute risks and negative outcomes.

What do we already know?

Previous research in this area has focused on whether collective decision-making results in a better decision overall. In some circumstances this process is helpful, but other times a group can get derailed and make a non-optimal decision. Since group decisions aren’t necessarily better in terms of accuracy, it is important to understand why we bother with them at all. After all, we like to have a choice when deciding what kind of product to buy, or what career to pursue. Some decisions are made together out of social obligation or a sense of fairness, but this may not account for all of the collective decision-making situations we observe.

What’s new?

The authors propose that one of the main reasons that individuals make decisions collectively is because it minimizes the risk taken by any one member. It’s what animals do when they herd or flock together, making it less likely that any one member is attacked (known as the dilution effect). Humans, even when they are not in physical danger, are very averse to certain emotional risks, especially regret or responsibility for a negative outcome. Making a decision as part of a group reduces the feeling of personal responsibility and can help us to cope with the stress of difficult decisions (like parents deciding whether or not to keep an injured child on life support). It may also protect us from social backlash (like when “whistleblowers” call out bad behavior of very powerful individuals). However, when taking the group perspective and not the individual perspective, the decrease of personal responsibility comes with its own problems: at worst, no one assumes responsibility for negative outcomes, and they are not addressed at all. Think of the bystander effect, where witnesses to an emergency situation are less likely to step in and help if others are present, or the tragedy of the commons, where individuals tend to over-use common resources.

What's the bottom line?

There are a number of factors that push us toward collective decision-making: social inclusion and fairness, the idea that we are smarter together, and, as El Zein and colleagues emphasize, protection from negative consequences. In the future, it will be important to evaluate the relative contribution of these different factors in the drive to collective decision-making. This will help us better understand the behavior of the different social groups and governing bodies that permeate human society. Perhaps then we’ll know when to say, “many hands make light work” and when to say, “too many cooks spoil the broth.”

El Zein et al. Shared responsibility in collective decisions. Nature Human Behavior (2019).Access the original scientific publication here.