Take a Break: How the Brain Chooses When to Explore and When to Rest

Have you ever wondered why we feel comfortable in a familiar place or why going back to our favorite spots over and over again feels so good? Well, Dr. Paolo Botta, a former postdoc at Columbia University, and colleagues attempted to unravel some of the inner workings of the brain when it comes to rest and exploration. More specifically, Dr. Botta examined how neuronal activity correlates with periods of rest when exploring new areas. Dr. Botta and colleagues followed the behavior of mice as they freely explored a new area. They specifically looked at where and how often these mice decided to exhibit arrest behavior, or, in other words, take a break during their explorations. While the arrest behavior alone is a fascinating phenomenon and provides insight into how mice explore new spaces, Dr. Botta and colleagues decided to go a step further and see which neurons in the brain are important for this arrest behavior. They decide to home in on an area of the brain called the Nucleus of the Basal Lateral Amygdala (BLA). This area has previously been shown to be involved in locomotor exploration, experience based learning, recognition of familiar areas.

With this information in hand, Dr. Botta and colleagues began by identifying whether BLA neurons are active during arrest behavior. To this end, they gave mice access to both their home cages and a large open area for five days and allowed them to freely explore the large open area during this period. BLA neuronal activity was monitored in the mice by measuring calcium levels, with higher calcium levels indicating neuronal activity (Figure). The researchers observed an increase in calcium in BLA neurons during arrest behavior, which means that BLA neurons are involved in this type of behavior.  However, do these neurons actually cause the arrest behavior? To answer this question, Dr. Botta and colleagues either activated or inhibited the neurons using optogenetics. Optogenetics is a technique in which neurons are stimulated by light. So, by turning different lights on and off, the researchers were able to either activate or inhibit BLA neurons whenever they wanted to. When they activated the BLA neurons, the mice decreased their speed and experienced more arrest behavior. When they inhibited the BLA neurons, the mice had an increase in movement speed. After seeing how turning BLA neurons on and off affected behavior, they concluded that the BLA neurons are important for inducing arrest behavior.

At this point, Dr. Botta and colleagues have revealed that BLA neuronal activity occurs specifically during these arrest behaviors and that their activity is important for the onset of the arrest. However, their curiosity did not stop there. They began to wonder whether BLA activity changed when the mice exhibited arrest behavior, or took breaks in more familiar areas. To figure this out, Dr. Botto and colleagues tracked exactly where the mice explored and counted how many times the mice exhibited arrest behavior in areas that they previously explored. With this experiment, they realized that the mice were more likely to exhibit arrest behavior in areas previously visited. So, mice, like humans, have favorite spots and they like to rest in those spots! After seeing that the mice have favorite spots, Dr. Botto and colleagues went on to examine the BLA neuronal activity in these familiar areas. They found that there was an increase in neuronal activity in these familiar areas and the more a mouse revisited and exhibited arrest behavior in a specific area the more neuronal activity developed. In other words, the more often a mouse took a break in a specific area the more that correlated with BLA neuronal activity.

The amygdala has multiple nuclei, which consist of groups of cells that are important for specific roles. The Central Nucleus of the Amygdala (CEA) is a part of the amygdala that has previously been shown to be involved in immobility. BLA neurons also communicate with the CEA (Figure). Knowing that the BLA neurons are important for invoking arrest behavior and the CEA plays a role in immobility, Dr. Botta and colleagues were curious as to whether these BLA neurons that project to the CEA are the specific neurons involved in triggering arrest behavior. To see whether the BLA neurons that project to the CEA are the ones active during arrest behavior they used the combination of calcium imaging and optogenetic techniques previously mentioned. With these techniques they were able to see that the BLA neurons that project to the CEA had an increase in neuronal activity during arrest behavior (Figure). This increase was not seen in BLA neurons that projected to other parts of the amygdala indicating that the BLA-CEA interaction is integral for the arrest activity. They also repeated the stimulation of the BLA neurons that project to CEA and observed an increase in arrest while inhibiting the same neurons resulted in an increase in movement, further confirming the need of this BLA-CEA interaction to induce arrest behavior.

Overall, Dr. Botto and colleagues discovered that BLA neurons that communicate with the CEA are important for arrest behavior, particularly in familiar places. This behavior seems to be extremely important for allowing a mouse to orient itself and properly explore novel surroundings. Maybe humans have a similar pathway that we use when wandering around. Could my BLA be the reason why I always go to the same cafes after a long walk or stop in the same part of the park while walking my dog? Are our BLA neurons just firing away while we rest? 

Figure: BLA neuronal activity during exploratory vs arrest behavior.      Left: Decreased activity in BLA neurons that communicate with the CEA results in increased exploratory behavior. Right: Increased BLA to CEA neuronal activity, indicated by calcium signaling, results in increased arrest behavior. Red colors indicate decreased BLA neuronal activity and increased exploratory behavior. Green colors indicate increased BLA neuronal activity and increased arrest behavior. BLA: Nucleus of the Basolateral Amygdala, CEA: Central Nucleus of the Amygdala

Plasticity inception in a nutshell

Have you ever realized that you remember experiences associated with strong emotions more vividly? For example, you probably remember what you ate at your (or a close friend’s) wedding, but not last Tuesday. However, these persistent memories are not always pleasant. People exposed to actual or threatened death, serious injury, or sexual violence can develop Post-Traumatic Stress Disorder (PTSD), which involves recurring memories or dreams of the traumatic event, bodily reactions to reminders and active avoidance of those reminders. Treatment for PTSD combines psychotherapy and medication, and it aims at enabling the person to understand their trauma and detach the triggers from the responses.

The area in your brain responsible for the formation of such emotional memories is called the amygdala (from the Greek word for almond, due to its shape, Fig. 1). It can modify the way it will respond to similar stimuli in the future, and it can also affect how other brain areas, like the medial prefrontal cortex or the hippocampus, do as well. This ability to change and adapt is called plasticity, and it can start with something as “simple” as a synaptic connection becoming stronger or weaker. There are higher levels of plasticity, though. If changes alter the potential response of a region to a future challenge, this plasticity of plasticity is called metaplasticity.

Human and rodent brain with highlighted amygdala, medial prefrontal cortex and hippocampus.
Fig. 1. Depiction of a human and a rodent brain. Highlighted areas are responsible for establishing emotional memories, fear conditioning and extinction. Modified from Sokolowski and Corbin 2012.

In the recent review “Intra-Amygdala Metaplasticity Modulation of Fear Extinction Learning”, CUIMC postdoc Dr. Rinki Saha and colleagues provide a comprehensive account of recent literature on metaplasticity in the amygdala in the context of fear conditioning, and how it may lead to plasticity in other connected brain regions.

Fear conditioning is a classic rodent model in neuroscience research that allows scientists to study the mechanisms that lead to associations between neutral stimuli and unpleasant stimuli. The general experimental layout is as follows: first, a neutral stimulus (a light or a tone, for example) is consistently paired to precede an aversive stimulus (like an electric foot shock). After this exposure, animals learn that the neutral stimulus (called conditioned stimulus) predicts the aversive one (called unconditioned stimulus) and they develop a fear response which they perform right after the neutral stimulus (life freezing in place). The experiment can continue to study how they learn to dissociate them once the stimuli stop being paired. For this second part, called fear extinction learning, the neutral stimulus is presented by itself (without pairing it to the aversive one), and researchers measure the time it takes the animal to stop performing the fear response.

In order to study the amygdala’s role in fear extinction, scientists can inject different drugs into it with very fine syringes (in a procedure called stereotaxic surgery, Fig. 2). By either activating or inhibiting different signaling pathways, they can elucidate what roles those molecules play in the fear extinction process. In addition, experiences like stress and trauma can interfere with this extinction learning, as evidenced in people who suffer from PTSD and in rodent models exposed to different stressful situations, both acute and chronic.

Depiction of a stereotaxic surgery in a rodent. Detail of injection in the amygdala.
Fig. 2. Depiction of a stereotaxic surgery in a rodent. The anesthetized animal is fixed on the frame of the stereotaxic instrument, which has very accurate rulers for the three dimensions. A very fine syringe is introduced through the skull into the brain to administer the drug or virus in a very precise way.
Made with BioRender.

This paradigm has been used by many to study metaplasticity, where the change that occurs is not a modification of the baseline response but rather of the response to a subsequent plasticity-inducing stimulation. For example, Dr. Saha herself showed that it is possible to alter fear extinction learning by injecting a virus into a subregion of the amygdala that disrupts inhibitory synapses. Importantly, this happened without modifying the initial fear conditioning or the anxiety level of the animals. In addition, they also showed that those alterations in inhibitory synapses in the amygdala led to independent changes in the medial prefrontal cortex, hindering its intrinsic plasticity. The same intervention caused increased resilience to acute trauma and improved the performance of a task dependent on another brain region, the hippocampus. Hence, a very targeted intervention in the amygdala can cause an array of effects across multiple brain areas.

This body of research has tremendous implications in our understanding of the brain and how to treat its diseases. On a very pragmatic sense, it should serve as a cautionary tale for researchers to take into account and consider the potential for “undesired” plasticity in more than one place as a response to certain interventions. But more importantly, it opens up potential therapeutic strategies for trauma-related disorders like PTSD, stress or fear. Changes in one small region can lead to widespread effects through its connections to other brain areas. Hopefully, we are a little bit closer to tricking the brain into equating those traumatic memories with what you ate last Tuesday.


Dr. Rinki Saha is a Postdoctoral Research Fellow in the Department of Psychiatry researching  stress, and one of CUPS’ social media managers.

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