Chronic Stress: What Does That Mean?

            If life is like a marathon, chronic stress is like running with ankle weights.

I know what you’re thinking – everyone is stressed, what’s the big deal?! Feeling stressed before giving a presentation, heading to a job interview, or going on a first date is normal and natural. These fall into what psychologists call “acute stress.” Chronic stress, however, is the prolonged feeling of stress that interferes with one’s life. Not only does it feel bad, but it’s also bad for the body. High levels of circulating stress hormones, including corticosterone, can deteriorate the body’s ability to function. This is scary stuff, so it’s important we understand it well.

How Does Memory Play In?

Bruce McEwen’s work focused on the effects of chronic stress on the body, and his team found that chronic stress can lead to a lapse in memory formation. Our ability to learn and adapt is crucial to our ability to function productively in the world and live a happy life. McEwen’s team, in an effort to understand just how stress affects memory, conducted an experiment in which rats were subjected to chronic stress. The effects on their brain were fascinating – but first, let’s take a deeper look into memory function…

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First, a Glimpse at the Hippocampus

The hippocampus is comprised of several types of neurons, including CA1, CA3, dentate gyrus, and mossy fibers. When information is first received by the brain, it comes to the hippocampus via the entorhinal cortex, and is then processed by the cells of the dentate gyrus and translated into information that the CA3 neurons of the hippocampus can compute. Mossy fibers transmit this information from the dentate gyrus to the CA3 neurons of the hippocampus. CA3 neurons transmit their information to CA1 neurons, where it proceeds to the region of the brain that is most associated with that memory. This pathway (dentate gyrus mossy fibers to CA3 to CA1) is a basic mechanism of memory storage. To understand how stress impacts memory, though, we have to go a little deeper.

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A Deeper Look at Memory: Long Term Potentiation

One of the most critical aspects of the hippocampal memory circuit is its plasticity, meaning its ability to change in response to the environment. Long term potentiation describes the brain’s process of making cells more excitable in response to inputs. NMDA receptors (which respond to glutamate, the brain’s most abundant excitatory neurotransmitter) populate the postsynaptic cell’s membrane (pictured below in as blue receptors on a green neuron). “Learning” is the process of strengthening connections between neurons by adding more NMDA receptors to the postsynaptic membrane. More NMDA receptors means lower levels of glutamate will be needed to excite the postsynaptic cell; and thus a memory is born!

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McEwen’s Rats

With all of this in mind, McEwen’s lab was interested in the role of chronic stress in hippocampal learning and memory formation. After repeatedly exposing a group of rats to stressful situations, the research team recorded the electrophysiological states of the rats, and found that rats who experienced chronic stress had decreased long term potentiation (LTP) in mossy fiber input into the Dentate Gyrus and in CA3 neuron input. Interestingly, mossy fiber inputs into the CA3 neurons were not affected

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So What Does This Mean for Us, The Chronically Stressed?

In order to understand what these findings mean for the state of our memory formation, we must take a closer look at the results from McEwen’s lab:

As you remember, Mossy fibers connect to both CA3 and dentate gyrus cells. What wasn’t mentioned earlier, however, was how the mossy fiber connections to the CA3 neurons are dependent on opioid peptides, not NMDA receptors, for their function, while mossy fibers connected to the dentate gyrus rely on NMDA receptors.

Because excitability in the mossy fibers’ connection to CA3 neurons didn’t change in chronically stressed rats, but connections to the DG did, we can conclude that stress must affect memory function via interactions with NMDA receptors.

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How Does Chronic Stress Do That?

When our body is stressed, the stress hormone corticosterone circulates throughout our body and our brain. McEwen’s lab postulated that long-term exposure to corticosterone suppresses NMDA receptors

I know what you’re thinking: How does it do that? The short answer is: we aren’t entirely sure, but we have a few ideas.

The amount of corticosterone in the brain affects the levels of extracellular glutamate in the hippocampus. NMDA is a glutamate receptor, so changes to glutamate levels have adverse effects on its receptors.

It’s also possible that elevated corticosterone levels interfere with LTP via inhibitory GABA receptors in the hippocampus, as GABAergic inhibition is crucial to the regulation of LTP and memory formation.  

Unfortunately, there’s no easy answer to the question of how exactly chronic stress affects our memory. As the fields of psychology and neuroscience build and intertwine, our understanding of the ways stress impacts our lives will continue to grow. For now, we can do our best to remove the ankle weights and keep on running.

References

Moorthi, P., Premkumar, P., Priyanka, R., Jayachandran, K.S., & Anusuyadevi, M. (2015). Pathological changes in hippocampal neuronal circuits underlie age-associated neurodegeneration and memory loss: positive clue toward SAD. World Biomedical Frontiers, 5, 62. 10.1016/j.neuroscience.2015.05.062.

Jonas, P., & Lisman, J. (2014). Structure, function, and plasticity of hippocampal dentate gyrus microcircuits. Frontiers in neural circuits, 8, 107. https://doi.org/10.3389/fncir.2014.00107

Pavlides, C., Nivòn, L., & McEwen, B. (2002). Effects of Chronic Stress on Hippocampal Long-Term Potentiation. HIPPOCAMPUS, 12, 2. https://doi.org/10.1002/hipo.1116

Header Image: LaBracio, L., (2016). How Stress Affects Your Brain (In TED-Ed GIFs). https://blog.ed.ted.com/2016/03/10/how-stress-affects-your-brain-in-ted-ed-gifs/ Accessed February 26, 2020.