Regulation of cholinergic basal forebrain development, connectivity, and function by neurotrophin receptors

Abstract

Cholinergic basal forebrain (cBF) neurons are defined by their expression of the p75 neurotrophin receptor (p75NTR) and tropomyosin-related kinase (Trk) neurotrophin receptors in addition to cholinergic markers. It is known that the neurotrophins, particularly nerve growth factor (NGF), mediate cholinergic neuronal development and maintenance. However, the role of neurotrophin signalling in regulating adult cBF function is less clear, although in dementia, trophic signalling is reduced and p75NTR mediates neurodegeneration of cBF neurons. Here we review the current understanding of how cBF neurons are regulated by neurotrophins which activate p75NTR and TrkA, B or C to influence the critical role that these neurons play in normal cortical function, particularly higher order cognition. Specifically, we describe the current evidence that neurotrophins regulate the development of basal forebrain neurons and their role in maintaining and modifying mature basal forebrain synaptic and cortical microcircuit connectivity. Understanding the role neurotrophin signalling plays in regulating the precision of cholinergic connectivity will contribute to the understanding of normal cognitive processes and will likely provide additional ideas for designing improved therapies for the treatment of neurological disease in which cholinergic dysfunction has been demonstrated.

Cholinergic Modulation of Glial Function During Aging and Chronic Neuroinflammation

“…The central cholinergic system helps regulate the vascularization of the brain (Sato and Sato, 1995;Van Beek and Claassen, 2011), and modulates cognition, specifically executive functions, attention, and memory (Levin and Simon, 1998;Ballinger et al, 2016;Prado et al, 2017;Solari and Hangya, 2018). The cholinergic neurons in the medial septum and the ventral diagonal band of the BF project to the hippocampus and are implicated in attention, short-term memory, and spatial learning (Boskovic et al, 2019). The cholinergic neurons of the brain stem (BS) project to the BF, the thalamus, and the ventral tegmental area (VTA), and are involved in regulating the waking state, behavioral responses as well as ocular saccades (Kobayashi and Isa, 2002;Newman et al, 2012;Mena-Segovia, 2016).…”

Fluoxetine and Ketamine Reverse the Depressive but Not Anxiety Behavior Induced by Lesion of Cholinergic Neurons in the Horizontal Limb of the Diagonal Band of Broca in Male Rat

“…One hundred ninety-two IgG-saporin is an immunotoxin that is directed against the rat p75 nerve growth factor receptor, a low-affinity neurotrophin receptor ( Boskovic et al, 2019 ). The cholinergic neurons of the basal forebrain specifically express p75 nerve growth factor receptor, and injecting 192 IgG-saporin into the HDB results in cholinergic cell loss and a depletion of ChAT activity in the HDB ( Figure 1A ).…”

Cellular birthdate predicts laminar and regional cholinergic projection topography in the forebrain

“…Furthermore, cholinergic projections could initially project broadly across cortical laminae and become refined to specific layers through a combination of synaptic pruning and programmed cell death. In cholinergic neurons, both these processes are regulated in part by the p75 neurotrophin receptor ( Barrett, 2000 ; Boskovic et al, 2019 ; Niewiadomska et al, 2011 ). Additionally, attractant or repellant cues secreted from cortical cells could play a key role in guiding cholinergic fibers to the appropriate layers.…”