Top-down projections of the prefrontal cortex to the ventral tegmental area, laterodorsal tegmental nucleus, and median raphe nucleus

Abstract

Anatomical and functional evidence suggests that the PFC is fairly unique among all cortical regions, as it not only receives input from, but also robustly projects back to mesopontine monoaminergic and cholinergic cell groups. Thus the PFC is in a position to exert a powerful top-down control over several state setting modulatory transmitter systems that are critically involved in the domains of arousal, motivation, reward/aversion, working memory, mood regulation, and stress processing. Regarding this scenario, the origin of cortical afferents to the ventral tegmental area (VTA), laterodorsal tegmental nucleus (LDTg), and median raphe nucleus (MnR) was here compared, by using the retrograde tracer cholera toxin subunit b (CTb). CTb injections into VTA, LDTg, or MnR produced retrograde labeling in the cortical mantle, which was mostly confined to medial, orbital, and lateral PFC subdivisions, along with rostral and mid-cingulate areas. Remarkably, in all of the three groups, retrograde labeling was densest in layer V pyramidal neurons of the infralimbic, prelimbic, medial orbital and frontal polar cortex. Moreover, a conspicuous lambda-shaped region around the apex of the rostral pole of the nucleus accumbens stood consistently out as heavily labeled. At almost all rostrocaudal levels through the PFC analyzed, retrograde labeling was strongest following injections into MnR and weakest following injections into VTA. Altogether, our findings reveal a broadly similar set of prefrontal afferents to VTA, LDTg, and MnR, further supporting an eminent functional role of the PFC as a controller of all major state setting mesopontine modulatory transmitter systems.

Alpha-synuclein pre-formed fibrils injected into prefrontal cortex primarily spread to cortical and subcortical structures and lead to isolated behavioral symptoms

“…We also found that PFF mice displayed reduced thigmotaxis at 12 mpi, with the same non-significant pattern observed at 16 mpi, which may suggest a difference in explorative and anxiolytic behaviors in the open field as a result of PFC PFF injections. Further, we also found that PFF mice learned quickly, but The rodent PFC is a highly connected brain region, sending projections to multiple cortical, subcortical, midbrain, and brainstem nuclei (Anastasiades & Carter, 2021;Souza et al, 2022). Our prior work suggested that human PFFs injected into PFC cause a consistent but limited pattern of α-syn pathology including PFC, temporal cortex, and striatum.…”

“…The rodent PFC is a highly connected brain region, sending projections to multiple cortical, subcortical, midbrain, and brainstem nuclei (Anastasiades & Carter, 2021; Souza et al, 2022). Our prior work suggested that human PFFs injected into PFC cause a consistent but limited pattern of α-syn pathology including PFC, temporal cortex, and striatum.…”

Hub structure in functional network of EEG signals supporting high cognitive functions in older individuals

“…This sophisticated top-down control approach supports high cognitive functioning (Edin et al, 2009 ; Jo et al, 2019 ). Moreover, recent studies showed that the top-down projections of frontal-polar structural/functional connectivity support the extensive cognitive functions (Souza et al, 2022 ) (reviewed in Tsujimoto et al, 2011 ). The high frontal BC in the theta band obtained in this study (see Figures 2 , 3 and Tables 4 , 5 ) implies the existence of this top-down control, which achieves high cognitive functioning.…”

A subcortical switchboard for exploratory, exploitatory, and disengaged states

“…In this study, we identify the MRN in the brainstem as a key switchboard for controlling exploitation, exploration and disengagement across instinctive and acquired behaviors. The MRN provides a neural nexus at the interface of internal state, affective and cognitive information from brain regions such as the hypothalamus, habenula and prefrontal cortex [15][16][17][18] . Alongside the dorsal raphe nucleus, it is a main source of the neuromodulator serotonin, which has been broadly implicated in behavioral flexibility, perseverative behavior and obsessive disorders 13,[19][20][21][22][23] .…”

“…This suggests a cooperative role of dorsal and median raphe nuclei in balancing interaction states 13,23 . Neocortical input to MRN originates predominantly from prefrontal areas such as anterior cingulate and orbitofrontal cortex 15,16 ( Supplementary Fig. 10 ), areas important for evaluation of expected costs and outcomes of different choices, and updating of value estimates while taking into account outcome uncertainty and other factors 3,4,7,8 .…”