Cholinergic basal forebrain neurons regulate fear extinction consolidation through p75 neurotrophin receptor signaling

Boskovic, Zoran; Milne, Michael R.; Qian, Lei; Clifton, Hamish D; McGovern, Alice E; Turnbull, Marion T.; Mazzone, Stuart B.; Coulson, Elizabeth J.

doi:10.1038/s41398-018-0248-x

Cited by 22 publications

(20 citation statements)

References 47 publications

(59 reference statements)

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“…Despite this, the authors reported a ten-fold increase in synaptic connectivity between cBF neurons and target cells in the prefrontal cortex, an outcome that could be reversed by re-expression of p75 NTR in adult cBF neurons [79], thereby confirming a role for p75 NTR in pruning adult cBF connections. By contrast, synaptic connections to the dorsal hippocampus were relatively rare, and septo-hippocampal synaptogenesis was unaffected by manipulation of p75 NTR expression [79]. These observations indicate that p75 NTR controls presynaptic mechanisms of cBF synapse formation.…”

Section: Effects Of Loss Of P75 Ntr Expression On Cbf Morphologymentioning

confidence: 95%

“…However, the increased cBF axonal density could also be due to the increased cBF neuronal number, rather than, or as well as, an increase in the size of individual neuronal arbors. Although this is difficult to accurately delineate, labelling of individual axonal arbors has revealed that the arbor size of MS/VDB cBF neurons innervating the hippocampus and prefrontal cortex is not substantially affected by the lack of p75 NTR cBF neuronal expression [79], suggesting that the previously reported increased innervation was due to the overlapping arbors of the additional surviving cBF neurons. Despite this, the authors reported a ten-fold increase in synaptic connectivity between cBF neurons and target cells in the prefrontal cortex, an outcome that could be reversed by re-expression of p75 NTR in adult cBF neurons [79], thereby confirming a role for p75 NTR in pruning adult cBF connections.…”

Section: Effects Of Loss Of P75 Ntr Expression On Cbf Morphologymentioning

confidence: 96%

“…Although this is difficult to accurately delineate, labelling of individual axonal arbors has revealed that the arbor size of MS/VDB cBF neurons innervating the hippocampus and prefrontal cortex is not substantially affected by the lack of p75 NTR cBF neuronal expression [79], suggesting that the previously reported increased innervation was due to the overlapping arbors of the additional surviving cBF neurons. Despite this, the authors reported a ten-fold increase in synaptic connectivity between cBF neurons and target cells in the prefrontal cortex, an outcome that could be reversed by re-expression of p75 NTR in adult cBF neurons [79], thereby confirming a role for p75 NTR in pruning adult cBF connections. By contrast, synaptic connections to the dorsal hippocampus were relatively rare, and septo-hippocampal synaptogenesis was unaffected by manipulation of p75 NTR expression [79].…”

Section: Effects Of Loss Of P75 Ntr Expression On Cbf Morphologymentioning

confidence: 96%

“…Not surprisingly, the cBF nuclei required for particular behaviours depend on the circuity involved in the task. MS/VDB cBF neurons are needed for hippocampal-dependent functions such as the detection of spatial cues, exploration and cue-dependent allocentric navigation [78], and prefrontal cortex-dependent fear extinction [79], whereas NBM cBF neuron-mediated neurotransmission is necessary for amygdala-dependent functions including fear conditioning (but not extinction), object recognition [59,80] and egocentric navigation (Hamlin, Boskovic and Coulson, unpublished).…”

Section: The Function Of Adult Cbf Neurons Cbf Neuronal Effects On Bementioning

confidence: 99%

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

et al. 2019

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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.

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Section: Effects Of Loss Of P75 Ntr Expression On Cbf Morphologymentioning

confidence: 95%

Section: Effects Of Loss Of P75 Ntr Expression On Cbf Morphologymentioning

confidence: 96%

Section: Effects Of Loss Of P75 Ntr Expression On Cbf Morphologymentioning

confidence: 96%

Section: The Function Of Adult Cbf Neurons Cbf Neuronal Effects On Bementioning

confidence: 99%

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

et al. 2019

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“…cBF neuronal lesioning in a range of mouse AD models worsens many features of AD, including promoting cognitive impairment, and increasing Aβ accumulation, plaque load and inflammation (as observed herein), as well as causing tau hyperphosphorylation, hippocampal degeneration, and reduced BDNF expression (Gil-Bea et al, 2012;Ramos-Rodriguez et al, 2013;Hartig et al, 2014;Laursen et al, 2014;Turnbull et al, 2018). On the other hand, AD model rodents with increased cBF connectivity (Boskovic et al, 2014;Boskovic et al, 2018;Qian et al, 2018) or those which are treated with muscarinic receptor agonists display cognitive improvements and significantly reduced age-dependent A accumulation and inflammation compared to control rodents (Fisher et al, 2016). Cholinergic activation of muscarinic receptors also stimulates non-amyloidogenic APP processing (Rossner et al, 1998), thereby regulating the levels of Aβ in the interstitial fluid (Welt et al, 2015).…”

Section: Cbf Degeneration Is An Early Ad Feature That Can Drive Othermentioning

confidence: 55%

Cholinergic basal forebrain degeneration due to obstructive sleep apnoea increases Alzheimer’s pathology in mice

Qian

Kasas

Milne

et al. 2020

Preprint

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Epidemiological studies indicate that obstructive sleep apnoea is a strong risk factor for the development of Alzheimer's disease but the mechanisms of the risk remain unclear. We developed a method of modelling obstructive sleep apnoea in mice that replicates key features of human obstructive sleep apnoea: altered breathing during sleep, sleep disruption, moderate intermittent hypoxemia and cognitive impairment. When we induced obstructive sleep apnoea in a familialAlzheimer's disease model, the mice displayed exacerbation of cognitive impairment and pathological features of Alzheimer's disease, including increased levels of amyloid-beta and inflammatory markers, as well as selective degeneration of cholinergic basal forebrain neurons.These pathological features were not induced by chronic hypoxia or sleep disruption alone. Our results also revealed that the neurodegeneration was mediated by the oxygen-sensitive p75 neurotrophin receptor and hypoxia inducible factor 1 alpha activity. Furthermore, restoring blood oxygen levels during sleep to prevent intermittent hypoxia prevented the pathological changes induced by the OSA. These findings provide a signalling mechanism by which obstructive sleep apnoea induces cholinergic basal forebrain degeneration and could thereby increase the risk of developing Alzheimer's disease, as well as providing a rationale for testing a range of possible prophylactic treatment options for people with obstructive sleep apnoea and hypoxia including increased compliance of continuous positive airway pressure therapy. Keywords obstructive sleep apnoea, intermittent hypoxia, basal forebrain, cholinergic neuron, Alzheimer's disease, hypoxia-inducible factor 1alpha, Abbreviations AD: Alzheimer's disease, Aβ: amyloid-beta, APP: amyloid precursor protein, BF: basal forebrain, HIF1α: hypoxia-inducible factor 1 alpha, MPT: mesopontine tegmentum, OSA: obstructive sleep apnoea, p75NTR: p75 neurotrophin receptor, REM: rapid eye movement sleep, UII-SAP: urotensin II-saporin Whole body plethymographyWhole body plethysmography has been used to record respiration during sleep and wake cycles in unrestrained, freely moving mice (Hernandez et al., 2012). The mice were placed in a plethysmograph chamber (Buxco FinePointe Series WBP, DSI) continuously filled with fresh air at room temperature. This approach provides an indirect measure of tidal volume, which is directly proportional to the cyclic chamber pressure signal produced during respiration in a sealed chamber.The mice were first allowed 30 min to acclimatize to the chamber, after which the recording session preceded for 3h. Arterial oxygen saturationThe arterial oxygen saturation was recorded on unrestrained awake mice either in room air or in the environmental chamber using the MouseOx Plus oximeter (Starr Life Sciences) in accordance with the manufacturer's instructions. Data were collected for at least 30 min and only used when no error code was given. Oxygen saturation levels were then calculated as an average per mouse, and per experimental ...

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Cholinergic projections to the preBötzinger complex

Biancardi,

Yang,

Ding

et al. 2023

J of Comparative Neurology

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Rhythmic inspiratory activity is generated in the preBötzinger complex (preBötC), a neuronal network located bilaterally in the ventrolateral medulla. Cholinergic neurotransmission affects respiratory rhythmogenic neurons and inhibitory glycinergic neurons in the preBötC. Acetylcholine has been extensively investigated given that cholinergic fibers and receptors are present and functional in the preBötC, are important in sleep/wake cycling, and modulate inspiratory frequency through its action on preBötC neurons. Despite its role in modulating inspiratory rhythm, the source of acetylcholine input to the preBötC is not known. In the present study, we used retrograde and anterograde viral tracing approaches in transgenic mice expressing Cre‐recombinase driven by the choline acetyltransferase promoter to identify the source of cholinergic inputs to the preBötC. Surprisingly, we observed very few, if any, cholinergic projections originating from the laterodorsal and pedunculopontine tegmental nuclei (LDT/PPT), two main cholinergic, state‐dependent systems long hypothesized as the main source of cholinergic inputs to the preBötC. On the contrary, we identified glutamatergic and GABAergic/glycinergic neurons in the PPT/LDT that send projections to the preBötC. Although these neurons contribute minimally to the direct cholinergic modulation of preBötC neurons, they could be involved in state‐dependent regulation of breathing. Our data also suggest that the source of cholinergic inputs to the preBötC appears to originate from cholinergic neurons in neighboring regions of the medulla, the intermediate reticular formation, the lateral paragigantocellularis, and the nucleus of the solitary tract.

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Cholinergic basal forebrain neurons regulate fear extinction consolidation through p75 neurotrophin receptor signaling

Cited by 22 publications

References 47 publications

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

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

Cholinergic basal forebrain degeneration due to obstructive sleep apnoea increases Alzheimer’s pathology in mice

Cholinergic projections to the preBötzinger complex

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