The complexities of the brain are still largely unrevealed. Associations between neuronal decline with age and the onset of disease have been identified, but the specific mechanisms that regulate this decline are still unknown. Between neuron morphological changes, alterations of neuronal signals, and accumulation of protein masses in various brain regions, the realms of research are far and wide. As brain functions are responsible for approximately 20% of the body’s energy usage, further understanding of neurological function is essential for ensuring a longer and healthier life.
In the first of a series of lectures associated with the graduate Geroscience course at the Buck Institute, Dr. Jennifer Garrison shed light on the field of neuropeptides and what is known about their roles in the aging process. These peptides are responsible for communicative signals between neurons and other regions of the body. Neuropeptide signaling changes with age, and frequently these changes induce detrimental effects in neurons. They are packaged in large dense core vesicles and cleaved by enzymes at each end to reach their mature forms, which then interact with G protein-coupled receptors to induce signaling. These receptors can be local, but may also be found in other regions of the body, which means that malfunction in a given neuropeptide’s production or transport can result in dysfunction in multiple systems.
Interestingly, levels of the neuropeptide oxytocin are decreased in old mice plasma. Furthermore, knocking out oxytocin can diminish the formation of new muscle fibers upon injury induction, providing evidence to the possibility that age-related decreases in oxytocin can cause an age-related inability to regenerate muscle. Another neuropeptide that decreases with age is gonadotropin-releasing hormone (GnRH1), which is linked to inflammation and the stress response. This study showed that injection of GnRH1 into the brains of older mice restored neurogenesis in the hippocampus (the memory- forming center of the brain), which is a process known to decrease with age. The effects of altered neuropeptide levels can be profound, as is seen in the example of montane and prairie voles. Differing levels of vasopressin and oxytocin result in drastically differing social patterns, despite similar genetics between the two species. Such subtle differences in the regulation of neuropeptides are just an example of why it’s important to understand how alteration in neuropeptide signaling with age can contribute to a potential decline in health.
There are a number of challenges that face researchers focused on neuropeptides. Processing at both ends of peptides makes labeling difficult, and thus tracking neuropeptide activity becomes a complicated task. Further, a particular peptide may interact with multiple receptors or have redundant functions with other peptides, thus preventing a simple knockout experiment from being effective or easy to interpret.
To circumvent some of these complications, a number of approaches are frequently used. For example, a common practice is to look at brain slice cultures in vitro. Through this method, particular regions of brain tissue can be analyzed to observe various neuropeptide signals within that region. Some drawbacks, however, are that introducing bulk peptides to the culture does not show an in vivo response, and thus it’s difficult to see how neuropeptides affects the organism as a whole. Another method regularly utilized is bulk peptide intracerebroventricular (ICV) infusion. This particular process allows for analysis of an in vivo response to peptides. The difficulties of this method, however, are that it is difficult to observe specific neuron responses, and this method provides no indication as to the natural origins of the specific signals being studied.
To study the effects of various neuropeptides, the Garrison lab uses Caenorhabditis elegans as a model organism. Of particular interest to their work are the timing of signals, the locations, distance between release and reception of a peptide, and peptide degradation processes. Utilizing various chemicals and light responses, they have been able to stimulate peptide release and visualize the functional targets. The use of microfluidic devices allows for behavioral tracking of worms when various peptides are stimulated, which provides a better understanding of the way the peptides function.
The study of neuropeptides has been largely difficult due to technical and biological limitations, but novel techniques will provide the possibility of a “biochemical roadmap” more likely in the not-so-distant future. Understanding the processes by which neuropeptides are expressed, transported, and received can provide a huge boost to the overall understanding of the aging process by elucidating the mechanisms that they regulate. It’s not unrealistic to think that in the future neuropeptide therapeutics can help ease the age-related cognitive decline and dysfunction.