The Journey of Migrating Neurons in the Temporal Lobe: the long road home
By Shreyas Srinivasan
The human brain is an intricate organ that commands our day to day tasks. From basic actions such as reflexes to the most complex actions such as consolidating memory, abstract thought, or reasoning, the brain exemplifies the epitome of biological engineering. Though we collectively refer to the brain as the “control center,” the real heroes behind this organ are 4 lobes: frontal, parietal, temporal, and occipital. Each of these lobes are responsible for a unique category of functions. The frontal lobe is imperative in emotions, impulse control, judgment, motor function, and sexual behaviors. The parietal lobe is important in processing and interpreting sensory stimuli(e.g., temperature & pain). The occipital lobe is most important in visual processing. Out of the 4 lobes, this article will focus on the temporal lobe which is located on the side of the skull. The function of this lobe is to process auditory stimuli, language processing, and object/facial recognition. This being said, the functioning of these lobes aren’t mutually exclusive rather work in synchronicity to produce a behavior. For example, when we perceive a threatening stimuli such as a tiger, the stimuli activates both the occipital and frontal lobe.
This article interestingly researches a cortical structure that is part of the temporal lobe called the Entorhinal Cortex. The function of the Entorhinal Cortex is important in the consolidation of episodic memory and has high projections into the hippocampus. Specifically, this article analyzes how young neurons move into the Entorhinal Cortex and adjacent structures postnatally. Interestingly, this article highlights that the migrating cells are derived from the caudal ganglionic eminence, which is a momentary structure from which neurons are produced. These migrating cells eventually become an inhibitory interneuron called LAMP5+RELN+. Connecting this cortical structure with neuropathology, the neurodegenerative disease Alzheimer’s is known to first affect the hippocampus and the Entorhinal Cortex and prior research work has indicated the loss of LAMP5+RELN+ cells in those affected by Alzheimer’s. The objective of this article is to explain dense scientific articles into assimilable explanations in the hopes of making these research findings accessible to the public.
The results derived from the study showed that the young neurons migrated into the Entorhinal Cortex until two or three years of age and not at older age groups (3 - 77 years). Having migrating young neurons even at older ages would have been an evolutionary mechanism that could have potentially counteracted the detrimental effects of Alzheimer’s. In such diseases, cortical degradation occurs eventually causing neuronal death. By having young neurons migrate into the Entorhinal Cortex during the degradation process, cognitive functioning could still be maintained. However as the study claims, this result has unfortunately not been derived.
Another very interesting result this study highlights is the concept of neuroplasticity due to the process of neurogenesis. Neurogenesis refers to the creation of neurons. By adding more neurons in the brain, the brain is more likely to strengthen its synapses and reorganize its functions. Typically, neuroplasticity is seen after a traumatic brain injury where the brain will alter its functions and adapt to the effects of the injury. By having neurogenesis in the Entorhinal cortex, toddlers that benefit from the migration of young neurons, can experience enhanced learning and memory formation.
The first question that arose when reading this article was “Has there been research done on the relationship between LAMP5+ and neurodivergence? Could it be that there is a dysfunction with the LAMP5+ that causes cognitive instability in such disorders?” To this question, the authors Dr. Nascimento and Dr. Sorrells responded with the following:
Dr. Nascimento: In recent years, our understanding of the different cell populations that make up the brain has advanced tremendously. Until recently, the best way to identify cell types was using antibodies against proteins believed to be uniquely expressed in specific cell populations of interest. However, this approach has some limitations: antibodies are not 100% reliable and may bind to other proteins besides the intended marker. Sometimes, there are significant variations between lots of antibodies. Perhaps the biggest limitation of using antibodies to study tissue composition is that it only allows us to visualize cells with well-defined markers, limiting our ability to see the whole picture.
More recently, single-cell RNA-seq has allowed scientists to go beyond antibodies and use the transcriptomic profiles of cells to map and understand their identities and states. In our study, we labeled the neurons we identified using a standardized nomenclature from the Allen Brain Institute. Ironically, despite using the whole transcriptome to assign cell identities, the nomenclature still relies on highly expressed genes as “markers”. LAMP5+ neurons do express LAMP5, but it’s unclear how this gene and its resulting protein are linked to the functions of this specific cell population. Notably, although LAMP5 is highly expressed in these neurons, it’s not a reliable marker for antibody-based studies: mature neurons express it mainly in their dendrites, making it nearly impossible to identify their cell bodies and study them. In the past, these cells would have been referred to as Reelin+ cells, a marker that we now know to be expressed in multiple neuronal populations.
So, although LAMP5+ neurons have always been present in our brains, we now have the tools to visualize and study them in greater detail. Some studies suggest that genes associated with neurodivergence may play a role in the migration and integration of young neurons into brain circuits—a process we describe as happening very late in the development of these cells.
Dr. Sorrells: I’m not aware of an association between LAMP5 protein or LAMP5 expressing cells and neurodivergence. I think your hypothesis is plausible though, because the loss of LAMP5 cells has been linked to cognitive decline in Alzheimer’s patients. There may be studies out there (probably transcriptomic-level analyses) that I am not aware of, or maybe some that will be forthcoming soon.
The second question that arose when reading this article was “Are there functional experiments that are being planned in the future to understand the role of lamp5 in these migrating neurons?” To this question, the authors Dr. Nascimento and Dr. Sorrells responded with the following:
Dr. Nascimento: Although we are not actively investigating the role of the LAMP5 gene in these neurons, me and Shawn Sorrells’ group are working to map the arrival and presence of these neurons in the entorhinal cortex and neighboring areas, and how this might differ in non-human primates, where the process is not as protracted.
Dr. Sorrells: We don’t have functional experiments planned, but it’s an interesting idea. We actually see very little of the LAMP5 protein being manufactured in the migratory-stage cells; it seems to be produced more after the cells have begun to settle. Fortunately we were still able to detect some of the LAMP5 gene transcript being produced in the more immature stages of the cells which helped us to have more confidence that this was the type of interneuron these cells would become. My understanding of LAMP5 is that not much is known about its cellular role, but it is lysosomal associated and some of the staining in older ages looks like it is in the synapses, so maybe it has a role in synapse formation or stabilization.
An implication of this research study is that toddlers that experience traumatic brain injuries to specifically the Entorhinal Cortex or the Hippocampus can show significant improvement cognitively with the help of neurons produced by the caudal ganglionic eminence. In future research studies, it would be interesting to see how potentially activating transient structures such as caudal ganglionic eminence can help produce neurons that can eventually make their way to degraded structures affected by Alzheimer’s.
References:
Nascimento, M.A., Biagiotti, S., Herranz-Pérez, V. et al. Protracted neuronal recruitment in the temporal lobes of young children. Nature 626, 1056–1065 (2024). https://doi.org/10.1038/s41586-023-06981-x
Migrating neurons in the human brain.