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Published in final edited form as: Biol Psychiatry. 2023 Oct 18;95(8):800–809. doi: 10.1016/j.biopsych.2023.10.007

5HT1A receptors on dentate gyrus granule cells confer stress resilience

John Gregory Bickle 1, Yifei Li 1, Amira Millette 1, Rushell Dixon 1, Serena Wu 1, Elena Carazo Arias 1, Victor Mari Luna 2, Christoph Anacker 1,3,4
PMCID: PMC10978305  NIHMSID: NIHMS1939550  PMID: 37863245

Abstract

Background:

Hyperactivity of granule cells in the ventral dentate gyrus (vDG) promotes vulnerability to chronic stress. However, which receptors in the vDG could be targeted to inhibit this hyperactivity and confer stress resilience is not known. The serotonin 1A receptor (5HT1AR) is a Gi protein coupled inhibitory receptor that has been implicated in stress adaptation, anxiety, depression, and antidepressant responses. 5HT1ARs are highly expressed in the DG, but their potential to promote stress resilience by regulating granule cell activity has never been examined.

Methods:

We exposed male and female mice expressing 5HT1ARs only in DG granule cells to 10 days of chronic social defeat stress (CSDS) and treated them with the 5HT1AR agonist, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) every day 30 min before each defeat throughout the CSDS paradigm. We then used whole-cell current clamp recordings, immunohistochemistry for the immediate early gene, cFos, corticosterone immunoassays, and behavioral testing to determine how activating 5HT1ARs on granule cells affects DG activity, neuroendocrine stress responses, and avoidance behavior.

Results:

We find that activating 5HT1ARs hyperpolarizes DG granule cells and reduces cFos+ granule cells in the vDG following CSDS, indicating that 5HT1AR activation rescues stress-induced vDG hyperactivity. Moreover, 5HT1AR activation dampens corticosterone responses to CSDS and prevents the development of stress-induced avoidance in the social interaction test and in the open field test.

Conclusions:

Our findings show that activating 5HT1ARs on DG granule cells can prevent stress-induced neuronal hyperactivity of the vDG and confer resilience to chronic stress.

Keywords: Hippocampus, stress vulnerability, neurotransmitter, HPA axis, sex differences

INTRODUCTION

Chronic stress is a major risk factor for the development of psychiatric disorders, including generalized anxiety, major depression, and posttraumatic stress disorder. Despite the high prevalence of these disorders, current treatments such as the widely used selective serotonin reuptake inhibitors (SSRIs) are only effective in around 1/3 of individuals receiving SSRIs as a treatment for anxiety or depression.(1,2) Psychiatric symptoms often manifest only after extended periods of stress when neurobiological impairments may have already progressed too much to be responsive to treatment. Identifying cellular and molecular mechanisms that protect from stress effects may thus have the potential to affect early stages of disease pathogenesis when neurobiological impairments are still reversible or preventable.

Previous work by us and others has shown that the dentate gyrus (DG) of the hippocampus is highly sensitive to the effects of stress,(3–6) and that stress-induced changes in DG neuronal activity cause behavioral abnormalities in mice.(3) In particular, chronic stress causes hyperactivity of ventral DG (vDG) granule cells,(3,7) and this stress-induced hyperactivity promotes avoidance behavior.(3) Accordingly, inhibiting vDG granule cells during chronic stress, either directly by using hM4Di designer receptors exclusively activated by designer drugs (DREADDs), or indirectly by increasing adult hippocampal neurogenesis, can prevent stress-induced avoidance and promote resilience.(3) While these findings indicate that vDG granule cell activity mediates individual differences in stress vulnerability, the molecular mechanisms regulating DG granule cell activity and stress resilience are largely unknown.

A large body of work has implicated the serotonin 1A receptor (5HT1AR) in stress adaptation, anxiety, depression, and antidepressant responsiveness.(8–12) The C(−1019)G polymorphism in the promoter region of the 5HT1AR gene is associated with depression and antidepressant response,(13,14) and germline deficient 5HT1AR knockout mice show more avoidance behavior and are less responsive to SSRIs.(15–17) In line with these studies, activating 5HT1ARs using systemic administration of its agonist, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), decreases stress-induced anhedonia and anxiety-like behavior in wild-type mice.(11,18,19) The 5HT1AR is a Gi protein coupled receptor that inhibits neuronal activity via Gi-mediated inhibition of cyclic adenosine monophosphate (cAMP) production and subsequent inactivation of calcium channels. Two types of 5HT1ARs regulate serotonin signaling in the brain: presynaptic autoreceptors on serotonin neurons in the raphé nuclei of the brainstem, which inhibit serotonin neurons and thereby reduce the release of serotonin at terminal projection sites; and postsynaptic heteroreceptors in limbic and cortical areas, which inhibit the activity of serotonin target cells.(20)

Postsynaptic 5HT1A heteroreceptors are densely expressed in the hippocampus, and 5HT1AR expression increases gradually along the hippocampal dorsal-ventral axis in mice.(21) Previous work has shown that chronic stress and corticosterone (CORT) decrease 5HT1AR binding,(22–27) protein,(28) and mRNA (29) expression in the rodent hippocampus. In contrast, interventions that alleviate stress-induced behavioral abnormalities, such as physical exercise, counteract stresss-induced reductions in hippocampal 5HT1AR levels.(28,30) On a functional level, activating 5HT1ARs specifically in the ventral hippocampus has anxiolytic effects.(31) While the specific cell type in the hippocampus responsible for this anxiolytic effect is not known, 5HT1ARs on DG granule cells are both necessary and sufficient for the behavioral responses to SSRI antidepressants.(32) This 5HT1AR-mediated antidepressant effect can also be recapitulated by directly inhibiting vDG granule cells using inhibitory hM4Di DREADD receptors in mice.(33)

Considering the role of DG granule cells in stress vulnerability, (3) we here tested whether activating Gi-coupled 5HT1ARs on these cells can inhibit stress-induced vDG hyperactivity and confer resilience. To this end, we used a transgenic mouse line that allowed us to activate 5HT1ARs specifically on DG granule cells during exposure to chronic social stress. (32,34) Our data show that DG-specific activation of 5HT1ARs during chronic social defeat stress inhibits hyperactivity of vDG granule cells, dampens neuroendocrine responses to stress, and prevents the emergence of stress-induced avoidance behavior. Together, our findings suggest that targeting 5HT1ARs in the DG can promote stress resilience.

MATERIALS AND METHODS

Experimental mice

Procedures were conducted in accordance with the US National Institutes of Health (NIH) Guide for the Care and Use of Laboratory Animals, the New York State Psychiatric Institute Institutional Animal Care and Use Committee (IACUC) at Columbia University, and the Research Foundation for Mental Hygiene (RFMH). Mice were housed in groups of 3–5 per cage with free access to food and water on a 12:12-h light/dark cycle. To target 5HT1ARs specifically to DG granule cells, we crossed germline-deficient for 5HT1AR knockout (1A KO) mice with mice expressing 5HT1AR under the DG granule cell specific Nrip2 promoter (DG1A+ mice) (Figure 1a,b).(34) Mice heterozygous for Nrip2 were bred with homozygous 1A KO mice to generate DG1A+ and 1A KO littermates. Male and female mice were used for experiments at 8–10 weeks of age.

Figure 1.

Figure 1.

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Activating 5HT1AR inhibits dentate gyrus (DG) granule cells. A) Genetic strategy to express 5HT1ARs in DG granule cells under the Nrip2 promoter in germline deficient 5HT1AR knockout mice. B) Autoradiography pictures showing lack of 5HT1ARs in 1A KO mice and rescue of 5HT1AR expression in the DG of DG1A+ mice. C) Whole-cell current clamp recordings show that bath application of 8-OH-DPAT hyperpolarizes granule cells in DG1A+ mice, but not in 1A KO mice. n=4–11; unpaired student’s t-test, ***p<0.001.

Drugs

Mice were injected subcutaneously with the 5HT1AR agonist, 8-Hydroxy-2-(di-n-propylamino) tetralin hydrobromide (8-OH-DPAT, 3 mg/kg/day, Sigma-Aldrich), or saline (0.9% NaCl) 30 min before each 5 min social defeat session on days 1 to 10 for resilience experiments, or every day for 10 days following CSDS for rescue experiments.

Receptor Autoradiography

5HT1AR autoradiography was performed as previously described.(16,32) Briefly, brains were extracted and immediately frozen on dry ice. Brains were cryosectioned at 18 μm, thaw-mounted on Superfrost slides (Fisher Scientific), and processed for 4-(2′-methoxyphenyl)-1-[2′-(n-2″-pyridinyl)-p-[125I]iodobenzamido]ethylpiperazine (125I-MPPI) autoradiography.(16,32)

Ex vivo electrophysiology

Whole-cell current clamp recordings of granule cells were performed on ventral DG slices (350 μm) at −70mV as previously described.(35) For each cell, membrane potential was recorded for 5 minutes before washing in 8-OH-DPAT (2 μM) and continued to be measured for another 15 minutes. Please see Supplemental Information for a complete description of electrophysiology procedures.

Chronic social defeat stress (CSDS)

CSDS experiments were conducted as previously described.(3,36) Experimental DG1A+ mice and 1A KO mice were paired with a novel male CD1 aggressor mouse for 5 min every day for a total period of 10 days. Female mice were marked with urine of male CD1 mice unknown to the CD1 aggressor on each day (as described in (37)). Aggressive behavior of CD1 mice towards females was quantified (Supp. Figure S1; please see also Supplemental Information). After each daily defeat session, experimental mice were housed in the same cage as the aggressor across a perforated plexiglass divider for 24h. Same-sex control mice were housed two per cage across a divider and paired with a novel control mouse every day.

Behavior Assays

All mice were single housed after the 10th day of defeat and subsequently tested in the Social Interaction (SI) test on day 11 and in the Open Field (OF) test on day 12 as previously described.(3) Please see Supplemental Information for a complete description of behavior assays.

Corticosterone EIA assay

Peripheral blood was obtained by submandibular blood draw 30 min after mice were defeated on days 1, 5, and 10. Blood was immediately centrifuged at 3000rpm for 15 min and the upper fraction was carefully isolated and stored at −80°C before corticosterone quantification using EIA assays (ArborAssays, Ann Arbor, MI) (see Supplemental Information).(38)

Brain tissue collection and processing for Immunohistochemistry

Seventy-two hours after completion of behavioral testing, defeated mice were exposed to an acute 5 min social defeat session and brains were collected 1h later to assess stress-induced cFos and Dcx+ adult-born neurons. Mice were anesthetized with ketamine/xylazine and transcardially perfused with saline and ice-cold 4% paraformaldehyde (PFA). Brains were postfixed overnight in 4% PFA at 4 °C, cryoprotected in 30% sucrose, frozen in optimum cutting temperature (OCT) compound and cryosectioned at 50 μm through the dorsal-ventral extent of the hippocampus. See also Supplemental Information.

Statistics

Behavior data, cFos, and Dcx expression were analyzed using Three-Way Analysis of Variance (ANOVA) to assess genotype, stress, and sex effects. Tukey’s post hoc test was used to compare individual groups when significant interactions were detected. Two-tailed t-test was used to analyze data from electrophysiological recordings. Corticosterone (CORT) data was analyzed using Two-Way and Three-Way Repeated Measures ANOVA (RMANOVA). Data was tested for normality using the Shapiro–Wilk test. Analyses were carried out using GraphPad Prism 6.0. We report detailed statistics for all experiments in Supp. Table 1.

RESULTS

Activating 5HT1ARs in the DG inhibits granule cell activity.

We first sought to determine if activating 5HT1ARs inhibits granule cell excitability. To this end, we used 5HT1AR knockout mice (1A KO) crossed with mice expressing 5HT1AR under the Nrip2 promoter specifically in DG granule neurons (referred to as DG1A+ mice, Figure 1a,b).(10) Quantification of autoradiography images in DG1A+ mice revealed that 5HT1ARs are rescued to 85.46±5.35% of wild-type (WT) levels (Supp. Figure S2). We then prepared hippocampal slices from DG1A+ and 1A KO male mice and used ex vivo whole-cell current clamp electrophysiology to record the membrane potential of individual DG granule cells before and after bath application of the 5HT1AR agonist, 8-OH-DPAT. Our data show that 8-OH-DPAT significantly hyperpolarized granule cells in DG1A+ mice, but not in 1A KO mice, confirming that 5HT1AR activation inhibits DG granule cell activity (Figure 1c).

Activating 5HT1ARs in the DG dampens neuroendocrine responses to CSDS.

Next, we wanted to test if activating 5HT1ARs on DG granule cells can buffer neuroendocrine responses to stress. We therefore injected male and female DG1A+ mice and 1A KO littermates with 8-OH-DPAT or saline 30 min before each 5 min daily defeat session. We then analyzed blood corticosterone (CORT) levels 30 min after each defeat on days 1, 5, and 10 (Figure 2a). In DG1A+ mice, 8-OH-DPAT had no effect on CORT levels in undefeated male and female mice (Figure 2b,d). CSDS increased CORT levels in DG1A+ males and females throughout the 10 days of the CSDS paradigm, and this stress-induced increase in CORT was significantly reduced in mice that were injected with 8-OH-DPAT compared to mice that received saline (Figure 2c,e). In 1A KO mice, CORT levels were also significantly increased by CSDS, but 8-OH-DPAT did not affect CORT levels in defeated males and females (Figure 2f,h) or in undefeated males and females (Figure 2g,i). Together, these data indicate that activating 5HT1ARs on DG granule cells can reduce CORT responses to CSDS.

Figure 2.

Figure 2.

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Activating 5HT1ARs reduces neuroendocrine responses to CSDS. A) Timeline of CSDS paradigm and blood sampling. B-E) 8-OH-DPAT effects on CORT levels in DG1A+ male and female mice. B) 8-OH-DPAT does not affect CORT levels in undefeated DG1A+ male mice. C) 8-OH-DPAT decreases CSDS-induced CORT levels in DG1A+ male mice. D) 8-OH-DPAT does not affect CORT levels in undefeated DG1A+ female mice. E) 8-OH-DPAT decreases CSDS-induced CORT levels in DG1A+ female mice F-I) 8-OH-DPAT does not affect CORT levels in undefeated or in defeated 1A KO male and female mice. n=3–7; *p<0.05 indicates main effect of 2-Way Repeated Measures ANOVA.

Activating 5HT1ARs in the DG prevents CSDS-induced social avoidance.

Because we saw that activating 5HT1ARs on DG granule cells dampens neuroendocrine responses to CSDS, we next wanted to investigate if 5HT1AR activation can also prevent the development of stress-induced avoidance behavior. We thus injected another cohort of DG1A+ mice and 1A KO littermates with 8-OH-DPAT or saline and then tested social avoidance in a social interaction (SI) task 24 hrs after the last defeat session. To determine if 5HT1AR activation during CSDS exposure prevents the development of social avoidance, we administered 8-OH-DPAT 30 min before each defeat session on each day but not during subsequent behavior testing in the SI task (Figure 3a).

Figure 3.

Figure 3.

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Activating 5HT1ARs prevents CSDS-induced social avoidance. A) Timeline of CSDS paradigm and social interaction (SI) testing. B-D) 8-OH-DPAT rescues CSDS effects on social avoidance in DG1A+ mice. B) Representative heatmaps of time spent in the SI arena during Trial 2 of the SI test in DG1A+ mice. C) 8-OH-DPAT treatment during CSDS increases social interaction time in defeated DG1A+ mice. D) 8-OH-DPAT treatment during CSDS decreases the time DG1A+ mice spent in the corner of the SI arena after CSDS. E-G) 8-OH-DPAT does not prevent CSDS effects on social avoidance in 1A KO mice. E) Representative heatmaps of time spent in the SI arena during Trial 2 of the SI test in 1A KO mice. F) 8-OH-DPAT treatment during CSDS does not affect social interaction time in 1A KO mice. G) 8-OH-DPAT treatment does not affect time spent in the corners in 1A KO mice. Males, n=7–19 (solid bars); Females, n=6–9 (striped bars); *p<0.05, **p<0.01 indicate main effects of 3-Way ANOVA.

During Trial 1 of the SI task, without a novel mouse present, neither CSDS nor 8-OH-DPAT affected the time that DG1A+ mice spent exploring the empty enclosure or the corners of the arena (Supp. Figure S3a–d). During Trial 2, with a novel mouse present in the enclosure, DG1A+ mice that had received daily saline injections during CSDS spent significantly less time interacting with a novel mouse (Figure 3b,c) and more time in the corners of the arena (Figure 3d), indicating that CSDS causes social avoidance behavior in these mice. This reduction in social preference is supported by an increase in the fraction of mice that spent less time with the novel CD1 mouse in Trial 2 than with the empty enclosure in Trial 1 (Supp. Figure S4; Supp. Table 2). DG1A+ mice that received 8-OH-DPAT 30 min before defeat on each day to activate 5HT1ARs spent significantly more time interacting with a novel mouse and less time in the corners of the arena compared to saline-treated DG1A+ mice (Figure 3c,d, last two bars; Supp. Figure S4). While males and females showed similar behavioral response to CSDS and 8-OH-DPAT, female mice spent overall less time in the interaction zone in each trial of the task (Figure 3; Supp. Figure S3).

In germline deficient 1A KO mice, defeated females spent less time exploring the empty enclosure during Trial 1 of the SI task while defeated males spent less time exploring the corners (Supp. Figure S3e–g). During Trial 2, with a novel mouse present, CSDS decreased social interaction time, increased the time spent in the corners, and increased the fraction of mice that spent less time with the novel CD1 mouse than with the empty enclosure (Figure 3e–g, Supp. Figure S4, Supp. Table 2). Treatment with 8-OH-DPAT did not rescue these effects of CSDS in 1A KO mice (Figure 3e–g; Supp. Figure S4). While males and females showed similar behavioral responses to CSDS and 8-OH-DPAT, females traveled overall longer distances in the arena than males (Supp. Fig. S5a,b,d).

To test if activating 5HT1AR in the DG after CSDS would also rescue CSDS effects on social avoidance, we exposed an additional cohort of DG1A+ and 1A KO male and female mice to 10 days of CSDS without treatment, and then injected 8-OH-DPAT or saline every day for 10 days following CSDS (Supp. Figure S6a). Treatment with 8-OH-DPAT following CSDS did not improve social interaction in either DG1A+ or 1A KO mice (Supp. Figure S6).

Collectively, these data indicate that activating 5HT1AR on DG granule cells during CSDS prevents the development of stress-induced social avoidance in both male and female mice.

Activating 5HT1ARs in the DG prevents CSDS-induced avoidance in the open field test.

To test if the stress resilient phenotype of 5HT1AR activation in DG1A+ mice can be seen in other tasks of avoidance that are not dependent on social interactions, we next tested mice in the open field (OF) task to analyze avoidance of brightly lit open spaces. DG1A+ mice that received daily saline injections during CSDS traveled significantly less distance in the center of the OF (Figure 4a–c) and DG1A+ males spent less time in the center of the arena than control mice (Figure 4d). In CSDS exposed DG1A+ mice, 8-OH-DPAT increased the distance traveled in the center and the time spent in the center of the OF arena compared to saline-treated mice (Figure 4c,d; last two bars). While these effects of 8-OH-DPAT were observed in both males and females, females spent overall less time in the center of the OF arena than males, and defeated females responded more strongly to 8-OH-DPAT than male mice (Figure 4c,d, last column).

Figure 4.

Figure 4.

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Activating 5HT1ARs prevents CSDS-induced avoidance in the open field (OF) test. A) Timeline of CSDS paradigm and OF testing. B-D) 8-OH-DPAT rescues CSDS effects on avoidance of the center of the OF in defeated DG1A+ mice. B) Representative movement paths of DG1A+ mice in the OF test. C) 8-OH-DPAT treatment increases the % distance traveled in the center of the OF arena in defeated DG1A+ mice. D) 8-OH-DPAT treatment increases the time spent in the center of the OF arena in defeated DG1A+ mice. E-G) 8-OH-DPAT treatment does not rescue CSDS effects on avoidance of the center of the OF in 1A KO mice. E) Representative movement paths of 1A KO mice in the OF test. F) 8-OH-DPAT does not affect the % distance traveled in the center of the OF arena in 1A KO mice. G) 8-OH-DPAT does not affect time spent in the center of the OF arena in 1A KO mice. Males, n=7–19 (solid bars); Females, n=6–9 (striped bars); *p<0.05, **p<0.01 indicate main effects and relevant post-hoc tests of 3-Way ANOVA.

In 1A KO mice, CSDS did not affect the distance traveled in the center of the OF but decreased the total time spent in the center (Figure 4e–g) and the total distance travelled in the arena (Supp. Figure S5f). 8-OH-DPAT treatment during CSDS had no effect on the distance traveled in the center (Figure 4f), the time spent in the center (Figure 4g), or on the total distance traveled in the arena (Supp. Figure S5f).

Together, these results indicate that 5HT1AR activation can also rescue stress-induced avoidance behaviors that are not of a social nature.

Activating 5HT1ARs in the DG decreases CSDS-induced granule cell hyperactivity.

We previously showed that CSDS causes hyperactivity of granule cells in the vDG, and that this hyperactivity in turn mediates the effects of stress on avoidance of another mouse in the SI task and of a brightly lit open space in the OF task. To test if activating 5HT1ARs inhibits CSDS-induced vDG hyperactivity, we exposed mice to an additional 5 min social defeat 72h following the completion of behavioral testing and collected brains 1h after this additional defeat. We then quantified the number of DG granule cells that were immunoreactive for the immediate early gene, cFos, as a proxy marker for neural activity (Figure 5a). In DG1A+ mice, CSDS did not significantly affect the number of cFos+ granule cells in the dorsal DG (dDG) (Figure 5b,c) but increased the number of cFos+ cells in the vDG (Figure 5d,e). 8-OH-DPAT treatment prevented this stress-induced increase in the number of cFos+ cells (Figure 5e, last two bars). In 1A KO mice, CSDS significantly increased the number of cFos+ cells in the dDG and vDG, and this effect was not rescued by 8-OH-DPAT (Figure 5f–i). CSDS and DPAT effects were observed in both male and female mice, although females showed a smaller increase in cFos+ cells in the vDG of DG1A+ and 1A KO mice than males. Together, these data indicate that activating 5HT1ARs on DG granule cells prevents stress-induced neuronal hyperactivity in the vDG.

Figure 5.

Figure 5.

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Activating 5HT1ARs prevents CSDS-induced vDG hyperactivity. A) Timeline of CSDS paradigm and brain collection for cFos immunohistochemistry. B-E) cFos expression in the DG of DG1A+ mice. B) Representative images of cFos expression in the dDG of DG1A+ mice. C) CSDS or 8-OH-DPAT do not affect cFos expression in the dDG of DG1A+ mice. D) Representative images of cFos expression in the vDG of DG1A+ mice. E) 8-OH-DPAT prevents the CSDS-induced increase in vDG cFos expression in DG1A+ mice. F-I) cFos expression in the DG of 1A KO mice. F) Representative images of cFos expression in the dDG of 1A KO mice. G) 8-OH-DPAT does not affect cFos expression in the dDG of 1A KO mice. H) Representative images of cFos expression in the vDG of 1A KO mice. I) 8-OH-DPAT does not affect the CSDS-induced increase in vDG cFos expression in 1A KO mice. Males, n=3–6 (solid bars); Females, n=3 (striped bars); *p<0.05, **p<0.01, ***p<0.001 indicate main effects of 3-Way ANOVA.

Activating 5HT1ARs in the DG does not rescue CSDS effects on adult hippocampal neurogenesis.

Our previous work had shown that CSDS decreases the number of doublecortin-positive (Dcx+) adult-born neurons in the DG and that increasing adult hippocampal neurogenesis confers stress resilience by inhibiting developmentally-born mature granule cells in the vDG.(3) To test if activating 5HT1ARs can prevent CSDS effects on neurogenesis, we quantified Dcx+ cells in a subset of brains used for the cFos quantification (Supp. Figure S7a). CSDS decreased the number of Dcx+ cells in the dDG and vDG of DG1A+ and 1A KO mice, and this effect was not rescued by 8-OH-DPAT in either genotype (Supp. Fig. S7b–i). These data thus suggest that the inhibition of vDG hyperactivity following 5HT1AR activation in DG1A+ mice is likely caused by a direct inhibition of vDG granule cell activity, and not by an indirect effect that is mediated by a 5HT1AR-dependent increase in adult hippocampal neurogenesis.

DISCUSSION

Identifying molecular mechanisms that can promote stress resilience may help develop novel strategies that could be used to prevent stress-induced psychopathology. Prior work by us and others has shown that stress causes hyperactivity of vDG granule cells,(3,7) and that inhibiting this hyperactivity using Gi protein coupled inhibitory DREADD receptors can confer resilience to CSDS.(3) Here, tested if we can stimulate endogenous receptors on DG granule cells that activate Gi signaling to inhibit the DG and promote stress resilience. We focused on the postsynaptic 5HT1A heteroreceptor because it is a Gi protein coupled inhibitory receptor that is highly expressed in DG granule cells.(21) We show that activating 5HT1ARs in the DG dampens neural activity and neuroendocrine responses to stress and prevents the development of avoidance behavior.

To test if 5HT1AR activation can inhibit DG granule cell activity and confer stress resilience, we used a previously developed mouse model in which 5HT1ARs are expressed only in DG granule cells (Figure 1a,b).(32,34,45) We first confirmed that 5HT1AR activation with the agonist, 8-OH-DPAT, indeed hyperpolarizes DG granule cells, and that this effect is absent in germline deficient 1A KO mice (Figure 1c). We then tested if activating 5HT1ARs alters neuroendocrine stress responses and found that 5HT1AR activation in the DG reduces CORT response to CSDS without affecting CORT levels in undefeated mice (Figure 2). Next, we tested if 5HT1AR activation would also protect from CSDS-induced avoidance behavior. Here, we found that 5HT1AR activation during CSDS prevented avoidance of a novel mouse and of a brightly lit open space (Figures 3,4), while activation of 5HT1ARs for the same time after CSDS did not rescue the avoidance phenotype (Supp. Figure S6). While we cannot exclude the possibility that longer periods of 5HT1AR activation may have antidepressant-like effects as in previous studies,(32) our data indicate that 5HT1AR activation during stress exposure is necessary to prevent avoidance.

Since our previous work had shown that direct inhibition of vDG granule cells during CSDS confers stress resilience,(3) we also tested if 5HT1AR activation reduces vDG hyperactivity following CSDS. Indeed, we found that CSDS increases the number of cFos+ granule cells most strongly in the vDG, indicating neuronal hyperactivity in this region, and this hyperactivity was rescued by activating 5HT1ARs with 8-OH-DPAT in DG1A+ mice (Figure 5). In 1A KO mice, CSDS caused a small but significant increase in the number of cFos+ cells also in the dDG, suggesting that CSDS may have more wide-ranging effects on DG hyperactivity in mice completely lacking 5HT1ARs. Together, these data confirm and extend our previous findings by highlighting a heightened responsiveness of the vDG to stress, and by showing that 5HT1AR activation can prevent this stress-induced hyperactivity.

Increasing adult hippocampal neurogenesis can confer stress resilience by inhibiting vDG granule cells.(3,48,49) We, therefore, tested if activating 5HT1ARs in the DG may also increase the number of adult-born neurons, which could account for some of the effects of 5HT1AR activation on stress resilience. While 10 days of CSDS decreases the number of Dcx+ adult-born neurons, 5HT1AR activation did not increase neurogenesis in either control or CSDS-exposed mice (Supp. Figure S7). While it is possible that longer periods of 5HT1AR activation may be needed to increase neurogenesis,(32) our findings suggest that the effects of 5HT1AR activation on granule cell activity and resilience are likely independent of changes in neurogenesis. Together with our previous findings,(3) these data indicate that inhibition of stress-induced DG hyperactivity can be achieved either through direct inhibition of DG granule cells, such as activating 5HT1AR and/or Gi signaling, or through indirect processes, such as increasing adult hippocampal neurogenesis.(3)

In addition to the absence of an 8-OH-DPAT treatment effect in 1A KO mice, 1A KO mice are more avoidant than DG1A+ mice in the OF test (Supp. Figure S8), similar to previous findings.(39) While CSDS reduced social avoidance in both, DG1A+ and 1A KO mice, the fraction of 1A KO mice that qualified as “resilient” based on an SI ratio >1 was higher in 1A KO than DG1A+ mice (Supp. Figure S4). These genotype differences may be a consequence of the increased time 1A KO mice spent with the empty enclosure in trial 1 of the task (Supp. Figure S3) and may reflect higher levels of novelty exploration, as previously described.(50,51) We also find that CORT levels stay elevated throughout CSDS in DG1A+ mice but decrease progressively in 1A KO mice (Figure 2), suggesting that CORT responses may adapt more quickly to stress in 1A KO mice. Previous work has demonstrated that 1A KO mice show blunted CORT responses to stress compared to wild-type mice,(52) possibly contributing to the different CORT responses in our study. It is also possible that the differences in the CORT release may result from different behavioral responses to the daily defeats, such as running away vs assuming a submissive posture.

While male and female mice responded similarly to CSDS and 8-OH-DPAT in CORT levels, avoidance behavior, and in the number of cFos+ and Dcx+ cells, we also found sex differences in some of our experiments. For example, DG1A+ females spent less time exploring the enclosure with or without a novel mouse in the SI task (Figure 3c; Supp. Figure S3c), while traveling overall longer distances (Supp. Figure S5a,b). DG1A+ females also spent less time in the center of the OF than males and responded more strongly to 8-OH-DPAT in this outcome measure (Figure S4d). At the neurobiological level, CSDS increased the number of cFos+ cells in DG1A+ and 1A KO females less than in males (Figure 5), and decreased the number of Dcx+ cells less in 1A KO females compared to males (Supp. Figure S7f–i). It is worth noting that the adaptation of the standard CSDS paradigm to females that we used in our study causes females to be defeated ~40% less than males (Supp. Figure S1). It is thus possible that the lower aggression experienced by females may result in smaller changes in neural activity and adult hippocampal neurogenesis compared to males. One limitation of our study is the relatively smaller number of females compared to males, which could have obscured potential sex-related effects.

In summary, our findings highlight a role for 5HT1ARs on DG granule cells as a mechanism to inhibit stress-induced vDG hyperactivity and confer resilience to chronic stress. While the specific targeting of 5HT1ARs in the DG without activating 5HT1ARs elsewhere in the brain is a translational challenge, our work highlights the role of serotonin signaling in the DG for stress resilience and suggests that molecular signaling mechanisms that inhibit DG activity could be promising targets to improve stress resilience. Such mechanisms could be further identified by dissecting downstream mediators of 5HT1AR and Gi signaling, or by using next generation sequencing approaches to identify novel pathways that regulate DG activity. Moreover, whether acute 5HT1AR activation or DG inhibition before stress is sufficient to confer resilience will be an important line of future investigations aimed at identifying novel targets to promote resilience in vulnerable individuals.

Supplementary Material

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Antibody rat anti-cFos Synaptic Systems cat# 226 017 1 in 500 dilution
Antibody rabbit-anti-Dcx Cell Signaling cat# 4604 1 in 1500 dilution
Antibody donkey anti-rat IgG Alexa 488 Jackson ImmunoResearch cat# 712-545-150 1 in 500 dilution
Antibody donkey anti-rabbit IgG Alexa 594 Jackson ImmunoResearch cat# 711-585-152 1 in 500 dilution
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Chemical Compound or Drug (+/−)-8-Hydroxy-2-(dipropylamino)tetralin hydrobromide,≥98% Sigma Aldrich H8520
Commercial Assay Or Kit DetectX Corticosterone Enzyme Immunoassay Kit Arbor Assyas cat# K014-H1/H5
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Organism/Strain Tg-Nrip2-Htr1aDG and Htr1a KO PMID: 17558402
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ACKNOWLEDGEMENTS

This project was supported by grants from the National Institute of Mental Health (NIMH) (R00MH108719, P50MH090964, R01MH126105) and a NARSAD Young Investigator Award to C.A. We would like to thank Dr. Cornelius T. Gross for kindly providing the DG1A+ and 1A KO transgenic mouse lines.

DISCLOSURES

Dr. Anacker has received research funding from Sunovion Pharmaceuticals and consulting fees from Ono Pharmaceuticals. All other authors report no biomedical financial interests or potential conflicts of interest.

Footnotes

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Supplementary information
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