How Do Pesticides Affect the Brain?

Post by Anastasia Sares

The takeaway

Pesticides kill unwanted weeds, pests, and fungi, often with molecules affecting the nervous system, but their mechanisms of activation can cause havoc in “non-target” species, including the humans that use them. Over the years, some pesticides have been banned for their toxic effects and new ones have been developed. Now we’re moving from recognizing acute poisoning situations to being able to assess long-term detriments, especially to cognitive function in humans.

How has pesticide use evolved?

Humans have used pesticides for a long time to increase crop yields or kill unwanted guests in their homes and bodies. We’ve tried everything from chrysanthemums to nicotine to arsenic to DDT. However, we walk a fine line with pesticide use: on the one hand, it can increase food security and decrease disease (for example, killing malaria-carrying mosquitoes), both of which preserve human life. On the other hand, the effects of pesticides may decrease biodiversity and have toxic effects on the human body.

When developing a pesticide, it would be ideal to come up with a chemical that disrupts only the pest’s biological processes and is otherwise “harmless.” Unfortunately, as we are all a part of the same tree of life and share many biological processes with other organisms, it is hard to find chemicals that match this ideal. Pesticides like DDT have been introduced and commercialized, only to be later banned (at least in some countries) when toxic effects were observed. But some pesticides act in more subtle ways or require accumulated doses, and the link to age-related diseases like Parkinson’s and Alzheimer’s has only emerged after longer periods of observation. Scientists have been hard at work trying to understand the more subtle mechanisms of pesticide neurotoxicity.

Oxidative stress is a common factor

Though different pesticides have different primary mechanisms for killing their target pest, many of them also cause oxidative stress in cells. Oxidative stress is a process that disrupts the normal functioning of mitochondria, the energy generators of the cell.

Normally, mitochondria convert molecules derived from our food and oxygen from our lungs into water and carbon dioxide through a series of controlled chemical reactions. The energy generated from these reactions is used to “charge up” molecules called ATP (adenosine triphosphate), and these ATP molecules travel throughout the cell and act as little batteries to provide energy for other chemical reactions that need it. Sometimes the electron transport chain fails and instead of producing carbon dioxide and water, it produces a rogue molecule with a negatively charged oxygen called a reactive oxygen species, or ROS. These ROS can leave the mitochondria and do damage to other parts of the cell, like membranes, proteins, or even DNA, which can lead to cell death (see this video at 5:15).

In a healthy cell, the activity of ROS is kept to a minimum, but pesticides can make the production of ROS more likely, causing the cell to lag in energy production and accumulate damage to DNA and proteins. This is the state of oxidative stress, and neurons are particularly sensitive to it.

What are some other mechanisms of neurotoxicity?

Pesticides can cause a myriad of other effects besides oxidative stress, including the accumulation of dementia-related proteins such as amyloid beta and tau, toxic buildups of signaling molecules like acetylcholine or glutamate, inflammation and immune cell activation, DNA damage and suppression (methylation), altered neuron structure and growth, and abnormal activation of growth factors, to name a few.

Some mechanisms of neurotoxicity are quite complex, and have only recently been brought to light: for example, glyphosate (a weed-killer) interrupts a biological process not present in human cells, which made it seem safe to use. However, it turns out that glyphosate can affect our gut bacteria which produce tryptophan, a precursor for the neurotransmitter serotonin. This change in the serotonin production chain can lead to anxious or depressive symptoms. Researchers will continue looking for complex reactions like these to better estimate the true effects of pesticide use. In addition, new research may need to focus on the synergistic effects of multiple pesticides instead of looking at one pesticide at a time.

What's the impact?

Regulation of pesticides is absolutely necessary to maintain the right balance between pest/disease control and human health, and continued research on the effects of pesticides is needed to inform those regulatory decisions.

References +

1. Aloizou, A.-M., Siokas, V., Vogiatzi, C., Peristeri, E., Docea, A. O., Petrakis, D., Provatas, A., Folia, V., Chalkia, C., Vinceti, M., Wilks, M., Izotov, B. N., Tsatsakis, A., Bogdanos, D. P., & Dardiotis, E. (2020). Pesticides, cognitive functions and dementia: A review. Toxicology Letters, 326, 31–51. https://doi.org/10.1016/j.toxlet.2020.03.005
2. Costa, L., G. (2008). Neurotoxicity of pesticides: A brief review. Frontiers in Bioscience, 13(13), 1240. https://doi.org/10.2741/2758
3. Richardson, J. R., Fitsanakis, V., Westerink, R. H. S., & Kanthasamy, A. G. (2019). Neurotoxicity of pesticides. Acta Neuropathologica, 138(3), 343–362. https://doi.org/10.1007/s00401-019-02033-9
4. Franco, R., Li, S., Rodriguez-Rocha, H., Burns, M., & Panayiotidis, M. I. (2010). Molecular mechanisms of pesticide-induced neurotoxicity: Relevance to Parkinson’s disease. Chemico-Biological Interactions, 188(2), 289–300. https://doi.org/10.1016/j.cbi.2010.06.003
5. Rueda-Ruzafa, L., Cruz, F., Roman, P., & Cardona, D. (2019). Gut microbiota and neurological effects of glyphosate. NeuroToxicology, 75, 1–8. https://doi.org/10.1016/j.neuro.2019.08.006

Closed-Loop Brain Stimulation Reduces Fear Responses

Post by Laura Maile

The takeaway

Patients with post-traumatic stress disorder (PTSD) have difficulty extinguishing fear responses, which leads to debilitating symptoms. Stimulating the brain’s reward circuitry while brain regions essential in memory consolidation are active can reduce fear.  

What's the science?

In PTSD, the brain’s ability to extinguish learned fear responses after removing a threat is diminished. Prior research indicates that the hippocampus and the mesolimbic reward network are important for memory formation and consolidation of fear memories. Closed-loop stimulation, or the automatic stimulation of a brain region when a device detects activity in a specific system, has been shown to enhance memory consolidation when used to activate the reward system. Though the involvement of regions such as the hippocampus, amygdala, and reward centers is known to be important in the maladaptive fear responses present in PTSD, the disease remains resistant to treatment. This week in Nature, Sierra and colleagues used hippocampal activity to initiate closed-loop stimulation of reward circuitry during extinction learning to augment the removal of fear memories. 

How did they do it?

The authors utilized fear conditioning to model PTSD in rats, using an auditory tone as the conditioned stimulus paired with foot shocks as the unconditioned stimulus. During extinction learning, animals were placed in a new context and repeatedly presented with the conditioned stimulus without the foot shocks.  Animals typically extinguish their fear response after repeated exposure to the conditioned stimulus without the associated foot shock and are considered to be in fear remission once they reduce their freezing to <20% of their initial freezing behavior. The authors used closed-loop stimulation of the medial forebrain bundle (MFB), a white matter tract central to the reward network, in response to hippocampal sharp-wave ripples to activate reward circuits during recall of extinction memories. Some rats received this closed-loop stimulation for one hour following the extinction protocol, while others received open-loop (continuous) stimulation or no stimulation. Persistence of fear reduction was tested by exposing animals to the conditioned stimulus again either 24 hours or 25 days following extinction. The authors then tested whether hippocampal sharp-wave ripples are necessary for fear extinction by silencing them with electrical stimulation of the ventral hippocampus following extinction procedures. Finally, they explored the involvement of Rac1, a protein involved in synapse formation, and dopamine D2 receptors in the basolateral amygdala by infusing a Rac1 inhibitor or a dopamine D2 receptor antagonist following each extinction session preceding the closed-loop stimulation. This allowed them to compare the freezing behavior of animals receiving different treatments during the extinction procedure.  

What did they find?

Compared to rats that received open-loop stimulation or no stimulation, rats in the closed-loop stimulation group showed reduced freezing during extinction learning, requiring fewer extinction sessions to achieve fear remission. This means that MFB stimulation in response to hippocampal sharp-wave ripples can help extinguish fear memories faster than controls and that this reduction in fear behavior persists over time. Silencing hippocampal sharp-wave ripples resulted in impaired extinction and increased freezing upon reexposure to the conditioned stimulus. This indicates that the hippocampal sharp-wave ripple activity is required to extinguish fear behavior. Finally, infusing either a Rac1 inhibitor or a dopamine 2 receptor antagonist into the BLA disrupted the closed-loop stimulation-induced improvement in fear extinction. This result suggests Rac1 signaling and dopamine D2 receptor activity in the BLA are involved in fear extinction mediated by neuromodulation of reward circuitry.  

What's the impact?

This study found that closed-loop stimulation of MFB reward circuitry in response to hippocampal sharp-wave ripple activity following fear extinction improved the animals’ extinction of fear over time. This means that enhancing the activity of reward circuitry by using biomarkers of memory consolidation as a cue can help animals displaying features of PTSD recover from cued fear conditioning. Deep brain stimulation, which has been successfully implemented in humans with a variety of neuropsychiatric conditions, could be a candidate for improved treatment of PTSD if utilized using the closed-loop design implemented in this study.  

Access the original scientific publication here.

How Sleep Deprivation Leads to Disrupted Neural Processing

Post by Meredith McCarty

The takeaway

Sleep deprivation leads to changes in sensory perception and arousal levels. The measured increase in neural population synchrony and decreased responses to auditory stimuli are similar across NREM sleep and sleep deprivation states. 

What's the science?

Sleep deprivation is known to alter cognitive performance in numerous ways, including the impairment of working memory, vigilance, cognitive speed, and executive attention. Despite the apparent cognitive impairments associated with sleep deprivation, the extent to which sleep deprivation alters neural processing remains underexplored. This week in Current Biology, Marmelshtein and colleagues recorded the auditory cortex of rats during different states of vigilance to determine what changes in neural activity are associated with sleep deprivation. 

How did they do it?

A total of 7 adult male rats were implanted with microwire arrays, and EEG and EMG electrodes and placed in a motorized running wheel apparatus for a ten-hour experimental paradigm. The microwire arrays allow for sampling of single neuron spiking activity, whereas the EEG and EMG electrodes allow for monitoring of slower brain rhythms across larger networks, as is relevant for determining arousal state. In order to induce vigilant and sleep-deprived states, the authors programmed the wheel to alternate between 3 seconds of forced running and 12-18 seconds of fixed wheel position over the first 5-hour experimental period. Following this 5 hours of sleep deprivation, the wheel was fixed for the final 5 hours in order to allow for a recovery sleep opportunity. Throughout the experiment, auditory stimuli trains were presented intermittently via speakers throughout the apparatus. This experimental design allows for the comparison of neural responses in the auditory cortex to auditory stimuli across vigilant, tired, and NREM and REM sleep. 

What did they find?

The authors compared many features of auditory processing across experimental conditions to determine whether arousal level had any effect on auditory processing. First, they found no significant effect of sleep deprivation on mean frequency tuning, onset responses, and spontaneous firing rate, which suggests that the rats’ arousal state had no effect on these neural responses. However, they found significant differences in population coupling measures, including increased population synchrony, and decreased entrainment to rapid auditory stimuli trains. These results suggest that sleep deprivation significantly affected how correlated individual neuronal firing rate was with the local population. When comparing neural activity during sleep deprivation and the recovery sleep experimental stages, they found that the neural effects of sleep deprivation - specifically increases in population synchrony - were very similar to NREM sleep. This suggests that low-arousal states, such as sleep deprivation and NREM sleep, lead to disrupted cortical processing of faster auditory inputs. 

What's the impact?

This study found that sleep deprivation leads to altered neuronal activity in early auditory sensory regions. While many aspects of neural processing were not affected by arousal level, the authors did reveal significant changes in population synchronization measures due to arousal level. The authors found similar increases in population synchronization and disrupted rapid sensory processing in both NREM and sleep-deprived states. These results have practical implications in the accurate monitoring of arousal levels, and theoretical implications in the continued study of how arousal and brain state influence brain activity.

Access the original scientific publication here.