Cholinergic modulation of dentate gyrus processing through dynamic reconfiguration of inhibitory circuits

Ogando, Mora B.; Pedroncini, Olivia; Federman, Noel; Romano, Sebastián A.; Brum, Luciano A.; Lanuza, Guillermo M.; Refojo, Damián; Marín‐Burgin, Antonia

doi:10.1016/j.celrep.2021.109572

Cited by 11 publications

(9 citation statements)

References 85 publications

(95 reference statements)

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“…Interestingly, a significant increase was observed in the density of c-Fos+ GCs (Figure 8F and 8G). This finding is consistent with recent reports that stimulating cholinergic afferents lowed the threshold for GC firing thus making them more excitable, potentially through interneuron-mediated disinhibition (Martinello et al, 2015; Ogando et al, 2021). By contrast, no significant difference was observed in the density of c-Fos+ GluR2/3+ MCs (Fig.…”

Section: Resultssupporting

confidence: 93%

“…To fill these knowledge gaps, our study demonstrated that activation of DB-DG cholinergic projections promotes quiescent rNSC activation and spatial memory. In addition, most studies on cholinergic modulation of the DG were performed using slice electrophysiology (Martinello et al ., 2015; Ogando et al ., 2021; Pabst et al ., 2016). Although these studies have undoubtedly provided valuable information on cholinergic regulation of specific types of DG cells, cell-type-specific signaling mechanisms underlying cholinergic activity-dependent modulation of DG is largely lacking.…”

Section: Discussionmentioning

confidence: 99%

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Basal forebrain cholinergic circuits orchestrate diverse cell types in the adult dentate gyrus to support neural stem cell function and spatial memory

Quintanilla

Song

Simon

et al. 2022

Preprint

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Dentate gyrus (DG) is a critical structure involved in spatial memory and adult neurogenesis, two distinct processes dynamically regulated by local circuits comprising diverse populations of DG cells. It remains unknown how these DG cells are orchestrated to regulate these distinct hippocampal functions. Here we report activation of a cholinergic circuit from the Diagonal Band of Broca to DG promotes quiescent radial neural stem cell (rNSC) activation and spatial memory. Furthermore, single-nucleus RNA-sequencing reveals broad transcriptomic changes across DG mature and adult-born cells in response to cholinergic-circuit activation. Notably, neuronal populations exhibit cholinergic-activity-induced molecular changes related to synaptic functions crucial for spatial memory; while rNSCs exhibit changes related to structural remodeling and neurogenic proliferation crucial for hippocampal neurogenesis. Electrophysiology and NicheNet analyses reveal granule cells, endothelial cells, and astrocytes as potential intermediaries for cholinergic regulation of rNSCs. Our findings reveal cell-type-specific signaling mechanisms underlying cholinergic regulation of distinct DG functions.

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Section: Resultssupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Basal forebrain cholinergic circuits orchestrate diverse cell types in the adult dentate gyrus to support neural stem cell function and spatial memory

Quintanilla

Song

Simon

et al. 2022

Preprint

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“…Therefore, we think that both subthreshold and Hebbian LTP cannot be practically induced without reduction of GABAergic inputs. Recently, it was reported that disinhibition is induced at MPP-GC synapses by septal acetylcholine release [ 38 ], whereas it is unknown whether similar disinhibition occurs at LPP-GC synapses. It remains to be elucidated whether Hebbian LTP can be induced when feedforward GABAergic inputs are inhibited under an influence of neuromodulator.…”

Section: Discussionmentioning

confidence: 99%

Burst firing is required for induction of Hebbian LTP at lateral perforant path to hippocampal granule cell synapses

Kim

et al. 2023

Mol Brain

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High frequency burst firing is critical in summation of back-propagating action potentials (APs) in dendrites, which may greatly depolarize dendritic membrane potential. The physiological significance of burst firings of hippocampal dentate GCs in synaptic plasticity remains unknown. We found that GCs with low input resistance could be categorized into regular-spiking (RS) and burst-spiking (BS) cells based on their initial firing frequency (Finit) upon somatic rheobase current injection, and investigated how two types of GCs differ in long-term potentiation (LTP) induced by high-frequency lateral perforant pathway (LPP) inputs. Induction of Hebbian LTP at LPP synapses required at least three postsynaptic APs at Finit higher than 100 Hz, which was met in BS but not in RS cells. The synaptically evoked burst firing was critically dependent on persistent Na+ current, which was larger in BS than RS cells. The Ca2+ source for Hebbian LTP at LPP synapses was primarily provided by L-type calcium channels. In contrast, Hebbian LTP at medial PP synapses was mediated by T-type calcium channels, and could be induced regardless of cell types or Finit of postsynaptic APs. These results suggest that intrinsic firing properties affect synaptically driven firing patterns, and that bursting behavior differentially affects Hebbian LTP mechanisms depending on the synaptic input pathway.

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“…A decline of the projections from the MS to the DG during aging has been previously described 15 . These cholinergic projections from the MS target both GCs and hilar interneurons, including NPY/SST-containing HIPP cells and parvalbuminergic basket cells, and axo-axonic cells 37 . HIPP cells are vulnerable to a cholinergic decline 27 and mediate cholinergic-induced NPY-Y1 receptor stimulation at the DG GCs 7 .…”

Section: Discussionmentioning

confidence: 99%

Increasing NPYergic transmission in the hippocampus rescues aging-related deficits of long-term potentiation in the mouse dentate gyrus

Klinger

Ángel

Çalışkan

et al. 2023

Preprint

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Loss of neuropeptide Y (NPY)-expressing interneurons in the hippocampus and decaying cholinergic neuromodulation are thought to contribute to impaired cognitive function during aging. However, the interaction of these two neuromodulatory systems in maintaining hippocampal synaptic plasticity during healthy aging has not been explored so far. Here we report profound sex differences in the Neuropeptide-Y (NPY) levels in the dorsal dentate gyrus (DG) with higher NPY concentrations in the male mice compared to their female counterparts and a reduction of NPY levels during aging specifically in males. This change in aged males is accompanied by a deficit in theta burst-induced long-term potentiation (LTP) in the medial perforant path-to-dorsal DG (MPP-DG) synapse, which can be rescued by enhancing cholinergic activation with the acetylcholine esterase blocker, physostigmine. Importantly, NPYergic transmission is required for this rescue of LTP. Moreover, exogenous NPY application alone is sufficient to recover LTP induction in aged male mice, even in the absence of the cholinergic stimulator. Together, our results suggest that in male mice NPYergic neurotransmission is a critical factor for maintaining dorsal DG LTP during aging.

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Cholinergic modulation of dentate gyrus processing through dynamic reconfiguration of inhibitory circuits

Cited by 11 publications

References 85 publications

Basal forebrain cholinergic circuits orchestrate diverse cell types in the adult dentate gyrus to support neural stem cell function and spatial memory

Basal forebrain cholinergic circuits orchestrate diverse cell types in the adult dentate gyrus to support neural stem cell function and spatial memory

Burst firing is required for induction of Hebbian LTP at lateral perforant path to hippocampal granule cell synapses

Increasing NPYergic transmission in the hippocampus rescues aging-related deficits of long-term potentiation in the mouse dentate gyrus

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