Prefrontal Cortex: A tale of two pathways
A combination of invasive and non-invasive techniques has allowed researchers to take a closer look at the two major neural pathways that connect the amygdala and the prefrontal cortex.
- University of Wisconsin-Madison, United States
- University of Rochester, United States
Ever since the ill-fated explosion in 1848 that sent a tamping iron through the prefrontal cortex of railroad worker Phineas Gage, inexplicably changing his personality, scientists have wanted to understand how the different regions of the brain are connected (Harlow, 1999; Van Horn et al., 2012). The task is immense because the computational power of the human brain lies not only in its billions of neurons, but also in the connections between them. Short-term memory, decision-making, mood regulation, and other complex behaviors that depend on the prefrontal cortex (PFC) are all based on multiple, long-range connections between neurons.
The connectivity between the prefrontal cortex and the amygdala is believed to be critical for the regulation of emotion, and has been implicated in anxiety and mood disorders in humans (Kim et al., 2016; Tromp et al., 2012; Johansen-Berg et al., 2008; Riva-Posse et al., 2014). Importantly, invasive experiments on monkeys have revealed that the PFC and the amygdala are connected by two pathways: the amygdalofugal pathway and the uncinate fasciculus (Nauta, 1961; Price et al., 1987; Lehman et al., 2011).
Connectivity in the brain occurs through axons: projections of neurons that can extend over great distances to transmit information to target cells. Local activity in receiving neurons influences whether and how this information is passed on through output channels to other regions. Different techniques can be used to visualize axons extending between cells in the brain. Tract tracing studies in monkeys rely on the use of genetic or molecular markers, known as tracers, to follow the path of an axon. However, in order to visualize the tracers using a microscope, the brain has to be sliced and mounted on slides, making this a highly invasive technique. A neuroimaging technique called diffusion tensor imaging (DTI), also known as ‘tractography’, is non-invasive and can be used on humans.
Tractography produces images of the brain based on axon tracts – bundles of axons that travel in the same direction. This technique uses the fact that water diffuses in different directions in the brain depending on the structures it surrounds. This makes it possible to estimate the direction of the diffusion of water molecules along axons. Tractography works best when axons are myelinated and form large smooth tracts on the way to their destination. However, many pathways in the brain twist and turn, subdividing into smaller bundles, regrouping, and crossing one another. This makes tractography studies technically difficult due to problems with false negative and false positive findings.
Now, in eLife, Davide Folloni and co-workers at the University of Oxford and Radboud University Nijmegen (Jérôme Sallet, Alexandre Khrapitchev, Nicola Sibson, Lennart Verhagen and Rogier Mars) report on a study that combines data from tract tracing studies and DTI to more accurately visualize the connectivity between the amygdala and the PFC in monkeys and humans (Folloni et al., 2019).
Both the amygdalofugal pathway and the uncinate fasciculus curve and turn extensively, co-mingling with axonal pathways connecting other brain regions. The amygdalofugal pathway is particularly tricky, as it pierces an area of the forebrain known as the substantia innominata (meaning unnamed substance). As it goes through this region, the pathway splits into smaller axon bundles. Some of these axons leave the pathway here, innervating the cells within this area of the brain, while others continue on to the PFC. In this part of its route, the amygdalofugal pathway is crisscrossed by axonal tracts from other brain regions, which make it difficult to obtain clear images of the pathway using tractography.
Using DTI data from rhesus monkeys, Folloni et al. employed a probabilistic tractography method to estimate the most likely orientation of the axons as they cover the long distance from the amygdala to the PFC. Using known features of both the amygdalofugal pathway and the uncinate fasciculus, obtained from invasive tract tracing studies on macaques, they developed new methods for examining prefrontal connectivity in monkeys and humans. These tools helped to limit the problem of capturing crosstalk from intervening fiber systems, and allowed Folloni et al. to follow the predicted route of both pathways. They used known tract tracing results from macaques to validate their DTI approach, and then applied the validated DTI technique in humans. The results showed that the separation of the two pathways is conserved between humans and macaques.
In both species, they find that the amygdalofugal and uncinate pathways converge as they enter the lower PFC, before terminating in different regions of the frontal pole. The connectivity of both pathways was distinct from nearby control pathways. Folloni et al. then compared the connectivity ‘fingerprints’ of the two pathways in both species (i.e. the brain regions most and least targeted by the pathways), finding overall similarities but also subtle differences.
The findings from Folloni et al. underscore the critical importance of using nonhuman primates in psychiatric research due to the close anatomic match of evolutionarily expanded brains. Moreover, there is a critical need to validate and constrain DTI methodology using a ‘ground truth’ method. This new study shows the way forward by demonstrating the value of combining invasive and noninvasive data in cross-species analyses.
These new results can be useful for devising accurate biomarkers for psychiatric diseases and to understand how brain ‘wiring’ and myelination unfold with age in health and disease. Clinically, these methods may help identify pathways associated with specific symptom clusters found in different disorders, and help to provide individualized diagnosis. For example, some forms of depression may involve the amygdalofugal pathway, while other depressive illnesses, with different symptoms, might not. Localizing aberrant brain connectivity within a specific network linked to precise symptom profiles may help plan for emerging treatments such as deep brain stimulation or transcranial magnetic stimulation.
References
-
Passage of an iron rod through the head. 1848The Journal of Neuropsychiatry and Clinical Neurosciences 11:281–283.https://doi.org/10.1176/jnp.11.2.281
-
Fibre degeneration following lesions of the amygdaloid complex in the monkeyJournal of Anatomy 95:515–531.
-
BookThe limbic region. II. The amygdaloid complexIn: Björklund A, Hökfelt T, Swanson L. W, editors. Handbook of Chemical Neuroanatomy. Amsterdam: Elsevier. pp. 279–381.
-
Reduced structural connectivity of a major frontolimbic pathway in generalized anxiety disorderArchives of General Psychiatry 69:925–934.https://doi.org/10.1001/archgenpsychiatry.2011.2178
Article and author information
Author details
Publication history
Copyright
© 2019, Oler and Fudge
This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 7,899
- views
-
- 265
- downloads
-
- 2
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Prefrontal Cortex: A tale of two pathways
eLife 8:e51990.
https://doi.org/10.7554/eLife.51990
Further reading
-
- Neuroscience
Munc13 plays a crucial role in short-term synaptic plasticity by regulating synaptic vesicle (SV) exocytosis and neurotransmitter release at the presynaptic terminals. However, the intricate mechanisms governing these processes have remained elusive due to the presence of multiple functional domains within Munc13, each playing distinct roles in neurotransmitter release. Here, we report a coordinated mechanism in the Caenorhabditis elegans Munc13 homolog UNC-13 that controls the functional switch of UNC-13 during synaptic transmission. Mutations disrupting the interactions of C1 and C2B with diacylglycerol (DAG) and phosphatidylinositol 4,5-bisphosphate (PIP2) on the plasma membrane induced the gain-of-function state of UNC-13L, the long UNC-13 isoform, resulting in enhanced SV release. Concurrent mutations in both domains counteracted this enhancement, highlighting the functional interdependence of C1 and C2B. Intriguingly, the individual C1 and C2B domains exhibited significantly stronger facilitation of SV release compared to the presence of both domains, supporting a mutual inhibition of C1 and C2B under basal conditions. Moreover, the N-terminal C2A and X domains exhibited opposite regulation on the functional switch of UNC-13L. Furthermore, we identified the polybasic motif in the C2B domain that facilitates SV release. Finally, we found that disruption of C1 and C2B membrane interaction in UNC-13S, the short isoform, leads to functional switch between gain-of-function and loss-of-function. Collectively, our findings provide a novel mechanism for SV exocytosis wherein UNC-13 undergoes functional switches through the coordination of its major domains, thereby regulating synaptic transmission and short-term synaptic plasticity.
-
- Neuroscience
The perception of innocuous temperatures is crucial for thermoregulation. The TRP ion channels TRPV1 and TRPM2 have been implicated in warmth detection, yet their precise roles remain unclear. A key challenge is the low prevalence of warmth-sensitive sensory neurons, comprising fewer than 10% of rodent dorsal root ganglion (DRG) neurons. Using calcium imaging of >20,000 cultured mouse DRG neurons, we uncovered distinct contributions of TRPV1 and TRPM2 to warmth sensitivity. TRPV1’s absence – and to a lesser extent absence of TRPM2 – reduces the number of neurons responding to warmth. Additionally, TRPV1 mediates the rapid, dynamic response to a warmth challenge. Behavioural tracking in a whole-body thermal preference assay revealed that these cellular differences shape nuanced thermal behaviours. Drift diffusion modelling of decision-making in mice exposed to varying temperatures showed that TRPV1 deletion impairs evidence accumulation, reducing the precision of thermal choice, while TRPM2 deletion increases overall preference for warmer environments that wildtype mice avoid. It remains unclear whether TRPM2 in DRG sensory neurons or elsewhere mediates thermal preference. Our findings suggest that different aspects of thermal information, such as stimulation speed and temperature magnitude, are encoded by distinct TRP channel mechanisms.
