Stressful experiences differentially regulate immediate-early genes and stress hormone receptors in immature and mature dentate gyrus neurons

Hippocampal functions in memory and emotion are sensitive to stress. Stress and corticosteroids modulate neuronal activity and plasticity in the hippocampus and regulate its contributions to behavior. One feature of the hippocampus that is highly sensitive to stress is adult neurogenesis. Stress alters the proliferation and survival of adult-born neurons in the hippocampal dentate gyrus (DG). Furthermore, adult-born neurons modulate the behavioral response to stress. How newborn neurons respond to stress at a cellular level still remains relatively unexplored, but is important for understanding how they regulate behavioral responses. Here we examined whether two experiences that differ in the degree of stress, novel context exposure and physical restraint, alter levels of immediate-early genes (IEGs), mineralocorticoid receptors (MR) and glucocorticoid receptors (GR) in immature adult-born neurons and putative older neurons in the DG. We found that experience, particularly restraint stress, reduces levels of zif268 and MR in immature neurons but not older neurons. In contrast, both context exposure and restraint stress increased GR levels in immature neurons and mature neurons. These divergent cellular responses suggest that these two neuronal populations may have distinct functions in regulating the stress response. Introduction The dentate gyrus subregion of the hippocampus is comprised of a heterogeneous population of cells due to ongoing neurogenesis throughout adulthood. Adult-born neurons transition through defined developmental stages and, during a period of immaturity, they have enhanced synaptic plasticity and different patterns of activity compared to more mature neurons [1] [2] [3] [4] [5] [6]. One commonly-used measure of activity is the immediate-early gene (IEG) response to behavioral or physiological stimuli. IEGs are rapidly-induced following synaptic activity and promote plasticity that is required to store and process information [7]. Adult-born neurons show increased expression of IEGs as they mature and integrate into hippocampal circuits. For example, adultborn neurons gradually increase Fos expression until they reach similar rates as mature neurons [8]. However, zif268 expression shows a pronounced peak during cellular immaturity [2] and elevated expression in older adult-born neurons following learning tasks, compared to developmentally-born mature neurons [9]. The factors that recruit adult-born neurons during behavior remain unclear but may depend on stress. In response to a stressor, glucocorticoids are released and bind to GRs and MRs, which act via genomic and non-genomic mechanisms to alter neuronal function [10] [11]. Notably, even acute stressors are capable of producing longlasting changes in memory and behavior [12] [13] [14]. It is likely that glucocorticoiddependent signalling regulates adult-born neurons since they express GRs andMRs [15] [16], show enhanced survival in response to chronic stress [17], and require GRs for their functional maturation [18]. Since corticosteroid receptor levels vary across hippocampal subregions at baseline and in response to corticosterone treatment [19] [20], this raises the possibility that MR and GR levels may also differ between young and old neurons within the DG and endow them with distinct cellular functions. This could arise from many possible divergent transcriptional targets of MRs vs GRs [21], distinct functions in LTP where MRs promote post-stress LTP in the ventral hippocampus and GRs impair post-stress LTP in the dorsal hippocampus [22], or different roles in spine Stressful experiences differentially regulate immediate-early genes and stress hormone receptors in immature and mature dentate gyrus neurons DOI: 10.19185/matters.201719 Matters Select (ISSN: 2297-9239) | 2 formation/turnover [23] [24]. Differences in MR levels might also be expected to impact probability of synaptic glutamate release [25] and changes in GR levels could specifically impact IEG expression and memory consolidation [26] [27] [28] [29] [30]. Behavioral evidence also implicates adult-born neurons in the stress response. Preventing the addition of adult-born neurons leads to altered emotional responses and HPA output in response to stress [31] [32]. Furthermore, new neuron functions in context fear conditioning depend on the number of footshocks, suggesting stress-dependent recruitment [33]. However, it is unclear how stress impacts the IEG response in newborn neurons. In some instances, stressful experiences lead to Fos expression in immature neurons [34] [35]. In other cases, Fos expression appears selective to putative older neurons [36]. Interestingly, initial reductions in zif268 in immature DG neurons after water maze testing dissipate after extended training [4] [6]. This raises the question of whether the stress of a new, challenging experience might ,in fact, reduce IEG expression in newborn neurons. In short, further characterization is needed to clarify how cellular responses in the DG contribute to the stress-related changes in behavior. Objective To determine whether stressful experiences alter the expression of IEGs and nuclear levels of stress hormone receptors in immature adult-born neurons and older neurons in the DG.