Acute restraint stress decreases c-fos immunoreactivity in hilar mossy cells of the adult dentate gyrus

Moretto, Jillian N; Duffy, Áine; Scharfman, Helen E.

doi:10.1007/s00429-016-1349-z

Cited by 29 publications

(43 citation statements)

References 64 publications

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“…The low number of c-Fos-immunoreactive MCs in dorsal DG is consistent with prior studies of HCNOE (Bernstein et al, 2019; see also Duffy et al, 2013;Moretto et al, 2017) Next, we compared relatively rostral and more caudal coronal sections. Tukey's post-hoc tests revealed that in rostral sections, eDREADD mice (14.72 ± 1.87 cells) had significantly more hilar c-Fos cells per section than control (2.22 ± 0.31 cells) and iDREADD mice (1.90 ± 0.32 cells; all p values <0.001; Figure 10C).…”

Section: Hilar C-fossupporting

confidence: 79%

“…These findings are an important confirmation that eDREADD treatment increased neuronal activity of hilar neurons during this task. The hilar neurons were probably MCs because we previously found that HCNOE preferentially activates MCs compared to other hilar neurons after HCNOE (Duffy et al, 2013;Moretto et al, 2017;Bernstein et al, 2019) and DREADDs were preferentially expressed in MCs (Figure 1).…”

Section: Hilar C-fosmentioning

confidence: 89%

“…We analyzed c-Fos immunoreactivity across the septotemporal axis of the DG using criteria previously reported by our laboratory (Duffy et al, 2013;Moretto et al, 2017;Bernstein et al, 2019). Immunoreactive cells were manually counted at 16 x at similar locations across the septotemporal axis between subjects as previously described (Botterill et al, 2014;Moretto et al, 2017). The total number of c-Fos immunoreactive cells in the hilus and GCL were divided by the number of sections to determine the average number of cells per section.…”

Section: C-fos Quantificationmentioning

confidence: 99%

“…MCs have also been implicated in recognizing novelty in the environment such as the presence of new objects (Bernstein et al, 2019). Moreover, MCs are sensitive to restraint stress (Moretto et al, 2017), which is interesting because of studies linking the DG to affective behaviors, including anxiety (McEwen et al, 2016;Anacker and Hen, 2017).…”

Section: Introductionmentioning

confidence: 99%

“…Part of this uncertainty is due to conflicting reports about MCs in anxiety-like behaviors from previous studies (Jinde et al, 2012;Bui et al, 2018;Oh et al, 2019), possibly attributable to the different methods in targeting and manipulating MCs. In addition, the majority of MC studies to date have focused on male subjects (Jinde et al, 2012;Duffy et al, 2013;Moretto et al, 2017;Senzai and Buzsaki, 2017;Oh et al, 2019) or did not provide a clear view of sex differences (Danielson et al, 2017;GoodSmith et al, 2017;Bui et al, 2018). The focus on male subjects is problematic because there are known sex differences in GC structure, activity and synaptic plasticity (Hajszan et al, 2007;Zitman and Richter-Levin, 2013;Harte-Hargrove et al, 2015;Yagi and Galea, 2019) and some data showing sex differences in MCs (Guidi et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

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Bidirectional regulation of cognitive and anxiety-like behaviors by dentate gyrus mossy cells in male and female mice

Botterill

Vinod

Gerencer

et al. 2020

Preprint

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ABSTRACTThe dentate gyrus (DG) of the hippocampus is important for cognitive and affective behaviors. However, the circuits underlying these behaviors are unclear. DG mossy cells (MCs) have been a focus of attention because of their excitatory synapses on the primary DG cell type, granule cells (GCs). However, MCs also activate DG GABAergic neurons which inhibit GCs. We took advantage of specific methods and a gain- and loss-of function strategy with Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) to study MCs in diverse behaviors. Using this approach, manipulations of MCs could bidirectionally regulate behavior. The results suggest that inhibiting MCs can reduce anxiety-like behavior and improve cognitive performance. However, not all cognitive or anxiety-related behaviors were influenced, suggesting specific roles of MCs in some but not all types of cognition and anxiety. Notably, several behaviors showed sex-specific effects, with females often showing more pronounced effects than the males. We also used the immediate early gene c-Fos to address whether DREADDs bidirectionally regulated MC or GC activity. We confirmed excitatory DREADDs increased MC c-Fos. However, there was no change in GC c-Fos, consistent with MC activation leading to GABAergic inhibition of GCs. In contrast, inhibitory DREADDs led to a large increase in GC c-Fos, consistent with a reduction in MC excitation of GABAergic neurons, and reduced inhibition of GCs. Taken together, these results suggest that MCs regulate anxiety and cognition in specific ways. We also raise the possibility that cognitive performance may be improved by reducing anxiety.SIGNIFICANCE STATEMENTThe dentate gyrus (DG) has many important cognitive roles as well as being associated with affective behavior. This study addressed how a glutamatergic DG cell type called mossy cells (MCs) contributes to diverse behaviors, which is timely because it is known that MCs regulate the activity of the primary DG cell type, granule cells (GCs), but how MC activity influences behavior is unclear. We show, surprisingly, that activating MCs can lead to adverse behavioral outcomes, and inhibiting MCs have an opposite effect. Importantly, the results appeared to be task-dependent and showed that testing both sexes was important. Additional experiments indicated what MC and GC circuitry was involved. Taken together, the results suggest how MCs influence behaviors that involve the DG.

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Section: Hilar C-fossupporting

confidence: 79%

Section: Hilar C-fosmentioning

confidence: 89%

Section: C-fos Quantificationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Bidirectional regulation of cognitive and anxiety-like behaviors by dentate gyrus mossy cells in male and female mice

Botterill

Vinod

Gerencer

et al. 2020

Preprint

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Glucagon‐like peptide‐1 receptor differentially controls mossy cell activity across the dentate gyrus longitudinal axis

et al. 2022

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Understanding the role of dentate gyrus (DG) mossy cells (MCs) in learning and memory has rapidly evolved due to increasingly precise methods for targeting MCs and for in vivo recording and activity manipulation in rodents. These studies have shown MCs are highly active in vivo, strongly remap to contextual manipulation, and that their inhibition or hyperactivation impairs pattern separation and location or context discrimination. What is not well understood is how MC activity is modulated by neurohormonal mechanisms, which might differentially control the participation of MCs in cognitive functions during discrete states, such as hunger or satiety. In this study, we demonstrate that glucagon-like peptide-1 (GLP-1), a neuropeptide produced in the gut and the brain that regulates food consumption and hippocampal-dependent mnemonic function, might regulate MC function through selective expression of its receptor, GLP-1R. RNA-seq demonstrated that most Glp1r in hippocampal principal neurons is expressed in MCs, and in situ hybridization revealed strong expression of Glp1r in hilar neurons. Glp1rires-Cre mice crossed with Ai14D reporter mice followed by co-labeling for the MC marker GluR2/3 revealed that almost all MCs in the ventral DG expressed Glp1r and that almost all Glp1r-expressing hilar neurons were MCs. However, only ~60% of dorsal DG MCs expressed Glp1r, and Glp1r was also expressed in small hilar neurons that were not MCs. Consistent with this expression pattern, peripheral administration of the GLP-1R agonist exendin-4 (5 μg/kg) increased cFos expression in ventral but not dorsal DG hilar neurons. Finally, whole-cell patch-clamp recordings from ventral MCs showed that bath application of exendin-4 (200 nM) depolarized MCs and increased action potential firing. Taken together, this study identifies a potential neurohormonal mechanism linking a critically important satiety signal with activity of MCs in the ventral DG that might have functional effects on learning and memory during distinct states.

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Advances in understanding hilar mossy cells of the dentate gyrus

Scharfman

2017

Cell Tissue Res

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Hilar mossy cells (MCs) of the dentate gyrus (DG) distinguish the DG from other hippocampal subfields (CA1-3) because there are two glutamatergic cell types in the DG rather than one. Thus, in the DG, the main cell types include glutamatergic granule cells (GCs) and MCs, whereas in CA1-3, the only glutamatergic cell type is the pyramidal cell. In contrast to GCs, MCs are different in morphology, intrinsic electrophysiological properties, afferent input and axonal projections, so their function is likely to be very different from GCs. Why are MCs necessary to the DG? In past studies, the answer has been unclear because MCs not only excite GCs directly but also inhibit them disynaptically, by exciting GABAergic neurons that project to GCs. Results of new studies are discussed that shed light on this issue. These studies take advantage of recently available transgenic mice with Cre recombinase expression mostly in MCs and techniques such as optogenetics and DREADDs (designer receptors exclusively activated by designer drugs). The recent studies also address in vivo behavioral functions of MCs. Some of the results support past hypotheses whereas others suggest new conceptualizations of how the MCs contribute to DG circuitry and function. While substantial progess has been made, additional research is still needed to clarify the characteristics and functions of these unique cells.

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Acute restraint stress decreases c-fos immunoreactivity in hilar mossy cells of the adult dentate gyrus

Cited by 29 publications

References 64 publications

Bidirectional regulation of cognitive and anxiety-like behaviors by dentate gyrus mossy cells in male and female mice

Bidirectional regulation of cognitive and anxiety-like behaviors by dentate gyrus mossy cells in male and female mice

Glucagon‐like peptide‐1 receptor differentially controls mossy cell activity across the dentate gyrus longitudinal axis

Advances in understanding hilar mossy cells of the dentate gyrus

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