Projection neurons of the prefrontal cortex, their participation in the formation of various forms of behavior and expression in them of brain-derived neurotrophic factor

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Abstract

The prefrontal cortex (PFC) plays a key role in cognitive plasticity and is involved in various processes of higher nervous activity. At the same time, studying the processes underlying various forms of behavior in which PFC neurons participate is a non-trivial task. The associative functions of the PFC are associated with the nature of the connectivity of this structure with other areas of the brain, which, according to recent data, is much more complex than previously thought. Thus, it becomes clear that the axons of PFC projection neurons have many collaterals projecting to many different targets in the brain. In this review, we highlight the latest results in studying the connectivity of PFC neurons using the latest methods for analyzing projections and single-cell transcriptomes. Brain-derived neurotrophic factor (BDNF) plays an important role in the functioning of these neurons and their projection targets, but the transport of this neurotrophin by PFC projection neurons to structures where it is not locally expressed may be especially important. We review recent results mapping such neurons in the PFC, highlighting Bdnf expression and potential role in the pathogenesis of mental disorders.

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About the authors

U. S. Drozd

The Institute of Cytology and Genetic SB RAS

Email: lanshakov@bionet.nsc.ru
Russian Federation, Novosibirsk

Y. A. Frik

The Institute of Cytology and Genetic SB RAS; Novosibirsk State University

Email: lanshakov@bionet.nsc.ru
Russian Federation, Novosibirsk; Novosibirsk

A. V. Smagin

The Institute of Cytology and Genetic SB RAS

Email: lanshakov@bionet.nsc.ru
Russian Federation, Novosibirsk

D. A. Lanshakov

The Institute of Cytology and Genetic SB RAS; Novosibirsk State University; Novosibirsk Medical State University

Author for correspondence.
Email: lanshakov@bionet.nsc.ru
Russian Federation, Novosibirsk; Novosibirsk; Novosibirsk

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2. Fig. 1. Anatomy of the prefrontal cortex (PFC) in primates and rodents. (a) Human brain, medial view, color indicates Brodmann areas included in the PFC, line indicates approximate section level in Fig. 1b (preparation from the Anatomical Museum of the Faculty of Natural Sciences of Novosibirsk State University); (b) Frontal section of human brain (Allen Reference Atlas – Human Brain, atlas.brain-map.org [96]) and anatomical diagram of the names of the regions and Brodmann areas included in the PFC; (c) Coronal section of mouse brain: Nissl staining and subdivision of the PFC into main anatomical zones (Allen Reference Atlas – Mouse Brain, atlas.brain-map.org [97]).

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3. Fig. 2. Schematic diagram showing the production of a three-dimensional computer model of the branching of single neurons using fluorescence micro-optical sectional tomography (fMOST). PMT – photomultiplier detection tube.

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4. Fig. 3. Projection neurons of the prefrontal cortex. (a) Nissl staining and subdivision of the PFC into major anatomical regions (Allen Reference Atlas – Mouse Brain, atlas.brain-map.org [97]); (b) locations of PFC projection neurons according to Gao et al. [16] (https://mouse.braindatacenter.cn/). The size of the circles is proportional to the number of neurons of each subtype within an anatomical region; (c) some types of projection neurons are shown. Visible are the collaterals of IT neurons type 10 (marked with arrows and number 1), the subcortical collateral of IT neuron type 16 (marked with arrow and number 2), and the cortical collateral of PT neuron type 64 (marked with arrow and number 3). Individual neurons are indicated by different colors [16], (https://mouse.braindatacenter.cn/).

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5. Fig. 4. Schematic representation of the principles of single-cell transcriptomics. The tissue is broken into cells and then combined with barcoded beads in a microfluidic chip into an immiscible emulsion. Reverse transcription is performed by a matrix switching mechanism to incorporate specified sequences at the ends. This is followed by massively parallel NGS sequencing, computer processing, and clustering.

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6. Fig. 5. Expression of major marker genes. (a) – expression of major marker genes in PFC based on single-cell transcriptomics data (in situ hybridization data from the Allen Mouse Brain Atlas, mouse.brain-map.org [98]); (b) – some types of projection neurons and markers that are expressed predominantly in them are shown. Individual neurons are indicated by different colors. According to Gao et al. [16].

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7. Fig. 6. PFC projection neurons expressing the brain-derived neurotrophic factor Bdnf. (a) Bdnf expression in PFC. In situ hybridization data from the Allen Mouse Brain Atlas, mouse.brain-map.org [98] are shown. (b) A reporter construct was introduced by Ehinger et al. into mouse Bdnfcre as adeno-associated viruses with a capsid that transduces neurons retrogradely (retrograde tracers) into different areas of the striatum. (c) BDNF-expressing PFC neurons projecting to different areas of the striatum, identified by introducing retrograde tracers into the dorsomedial (DMS) and dorsolateral (DLS) striatum [54].

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8. Fig. 7. Regulation of Bdnf expression. (a) – diagram of the human locus in which Bdnf and Bdnf-as are located [64]. (b) – there are a large number of splice variants of Bdnf mRNA [68], which can be located in different compartments of the neuron and provide different local protein synthesis. (c) – antisense RNA (lncRNA) Bdnf-as binds to the polycomb protein EZH2 and causes histone methylation and transcriptional repression [71]. (d) – BDNF protein synthesis occurs differently, depending on the phase of synaptic potentiation (LTP), which is controlled by MNK kinase [66].

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