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. 2020 Dec;25(12):3278-3291.
doi: 10.1038/s41380-019-0514-1. Epub 2019 Sep 5.

The pathophysiological impact of stress on the dopamine system is dependent on the state of the critical period of vulnerability

Felipe V Gomes  1   2 , Xiyu Zhu  3 , Anthony A Grace  3
Affiliations

The pathophysiological impact of stress on the dopamine system is dependent on the state of the critical period of vulnerability

Felipe V Gomes et al. Mol Psychiatry. 2020 Dec.

Erratum in

Abstract

Unregulated stress during critical periods of development is proposed to drive deficits consistent with schizophrenia in adults. If accurate, reopening the critical period could make the adult susceptible to pathology. We evaluated the impact of early adolescent and adult stress exposure (combination of daily footshock for 10 days and 3 restraint sessions) on (1) midbrain dopamine (DA) neuron activity, (2) ventral hippocampal (vHipp) pyramidal neuron activity, and (3) the number of parvalbumin (PV) interneurons in the vHipp and their associated perineuronal nets (PNNs). Ventral tegmental area (VTA) DA neuron population activity and vHipp activity was increased 1-2 and 5-6 weeks post-adolescent stress, along with a decrease in the number of PV+, PNN+, PV + /PNN + cells in the vHipp, which are consistent with the MAM model of schizophrenia. In contrast, adult stress decreased VTA DA neuron population activity only at 1-2 weeks post stress, which is consistent with what has been observed in animal models of depression, without impacting vHipp activity and PV/PNN expression. Administration of valproate (VPA), which can re-instate the critical period of plasticity via histone deacetylase (HDAC) inhibition, caused adult stress to produce changes similar to those induced by adolescent stress, presumably by increasing stress vulnerability to early adolescent levels. Our findings indicate that timing of stress is a critical determinant of the pathology produced in the adult: adolescent stress led to circuit deficits that recapitulates schizophrenia, whereas adult stress induced a depression-like hypodopaminergic state. Reopening the critical period in the adult restores vulnerability to stress-induced pathology resembling schizophrenia.

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Figures

Figure 1 -
Figure 1 -. Impact of stress exposure during early adolescence or adulthood on DA system activity.
(a) Adolescent male rats were submitted to a combination of daily footshock (FS; through PD31–40) plus 3 restraint stress sessions (RS; PD31, 32, and 40). Extracellular recordings of VTA DA neurons and locomotor activity after saline or amphetamine (0.75 mg/kg) administration were evaluated between 1 and 2 weeks post-adolescent stress (through PD47–54). (b) Adolescent stress increased the number of spontaneously active VTA DA neurons with the recordings 1–2 weeks post-stress (naïve group: n = 8 rats, 0.87 ± 0.19 active DA neurons/track; stress group: n = 7 rats, 1.59 ± 0.15 active DA neurons/track; t13 = 2.92, p = 0.012), (c) but with no change in the firing rate (t115 = 0.79, p > 0.05) and (d) in the burst activity (t115 = 0.82, p > 0.05) of the identified spontaneously active DA neurons in the VTA (naïve group: n = 51 active DA neurons; stress group: n = 66 active DA neurons). (e) Consistent with the increased VTA DA neuron population, an increased locomotor response to amphetamine administration was also observed 1–2 weeks post-adolescent stress (n = 10 rats/group; t18 = 2.41, p = 0.03). (f) Long-term effects on DA system activity were also investigated 5 and 6 weeks post-adolescent stress (through PD75–82). (g) An increased number of spontaneously active VTA DA neurons was still present 5–6 weeks post-adolescent stress (naïve group: n = 6 rats, 0.98 ± 0.11 active DA neurons/track; stress group: n = 6 rats, 1.58 ± 0.07 active DA neurons/track; t10 = 4.63, p = 0.0009), (h) but with no change in the firing rate (t94 = 0.07, p > 0.05) or (i) in the burst activity (t94 = 1.10, p > 0.05) of active VTA DA neurons (naïve group: n = 39 active DA neurons; stress group: n = 57 active DA neurons). (j) In addition, an increased locomotor response to amphetamine administration was also observed 5–6 weeks post-adolescent stress (n = 10 rats/group; t18 = 2.42, p = 0.03). (k) Similar to the adolescent stress, adult male rats were submitted to a combination of daily footshock (FS; through PD65–74) plus 3 restraint stress sessions (RS; PD65, 66, and 74). Extracellular recordings of VTA DA neurons and locomotor activity after saline or amphetamine (0.75 mg/kg) administration were evaluated between 1 and 2 weeks post-adult stress (through PD81–88). (l) Contrary to the adolescent stress, adult stress decreased the number of spontaneously active VTA DA neurons 1–2 weeks post-stress (naïve group: n = 8 rats, 1.02 ± 0.07 active DA neurons/track; stress group: n = 10 rats, 0.69 ± 0.06 active DA neurons/track; t13 = 3.49, p = 0.003) (m) but with no change in the firing rate (t116 = 1.09, p > 0.05) and (n) burst activity (t116 = 0.12, p > 0.05) of the identified spontaneously active DA neurons in the VTA (naïve group: n = 61 active DA neurons; stress group: n = 57 active DA neurons), and (o) a previous exposure to adult stress did not exacerbate the locomotor response to amphetamine (n = 8–10 rats/group; t16 = 1.08, p > 0.05). (p) The impact of the adult stress on DA system activity was also investigated 5 and 6 weeks post-adult stress (through PD109–116). (q) No difference was found for the number of spontaneously active VTA DA neurons between naïve and stressed rat 5–6 weeks post-adult stress (naïve group: n = 7 rats, 1.12 ± 0.06 active DA neurons/track; stress group: n = 7 rats, 1.18 ± 0.09 active DA neurons/track; t12 = 0.01, p > 0.05), indicting a recovery of the hypodopaminergic state observed 1–2 weeks after the adult stress. Also, (r) no change in the firing rate (t104 = 0.08, p > 0.05) or (s) in the burst activity (t104 = 0.42, p > 0.05) of active VTA DA neurons (naïve group: n = 52 active DA neurons; stress group: n = 54 active DA neurons) was observed. Finally, (t) no change was observed in the locomotor response to amphetamine (n = 10 rats/group; t18 = 1.38, p > 0.05). Data are presented as mean ± SEM. *p < 0.05. Data are presented as mean ± SEM. *p < 0.05.
Figure 2 –
Figure 2 –. Impact of early adolescent stress on the maturational trajectory of putative parvalbumin interneurons in the vHipp.
(a) The cell count on putative PV interneurons and related maturational markers, PNNs, was performed in the ventral subiculum (vSub) of vHipp at different developmental time-points to assess the effect of stress on the maturational trajectory of the region. Specifically, the vSub was sampled at PD31 (first day of the stress paradigm), PD41 (one day after the stress paradigm), PD51 (1.5 weeks post-stress) and PD75 (adulthood; 5 weeks post-stress) (n = 4–6 rats/group). Large representative image capturing part of the vSub (10x); inset image showing two putative PV-positive interneurons - the top cell is not wrapped by the PNNs, whereas the bottom cell is clearly wrapped by PNNs, especially around somal region and proximal dendrites (40x). (b) For PV+ cells, one-way ANOVA revealed significant developmental change in naïve rats (F3,12 = 6.178; p = 0.0088), with adult rats (PD75) showing increased number of PV+ cells comparing to the early-adolescent rats at PD31 (Bonferroni post-hoc test, p < 0.05). Multiple t-test revealed that adolescent stress decreased the PV+ cell count at PD51 (t6 = 5.392; p = 0.0014) and PD75 (t6 = 4.286; p = 0.0052). (c) The total number of cells wrapped by PNNs was also under developmental regulation, as an 1-way ANOVA revealed significant effect of time-points on PNN+ cell count (F3,12 = 34.6; p < 0.0001). Bonferroni post-hoc analysis revealed significant increase in PNN+ cell count at PD51 (i.e. late adolescence, p < 0.05) and PD75 (i.e. adulthood, p < 0.05), comparing to PD31 (i.e. early adolescence). Stress-induced changes were only detected at PD51 (t6 = 5.391; p = 0.002), but not at PD75 (t6 = 0.44; p = 0.6940), suggesting a potential recovery during the late-adolescence to adulthood. (d) To assess the maturational trajectory of the putative PV interneurons, cell counting of PV and PNN co-labelled neurons was performed. Again, a significant developmental change was detected in naïve rats (F3,12 = 7.295; p = 0.0048), with PD51 and PD75 rats showing increased number PV+/PNN+ cells (p < 0.05 vs. PD31). Adolescent stress resulted in a significant reduction of PV/PNN co-labelled cell count at PD51 (t6 = 5.877; p = 0.0011), and a trend of reduction at PD75 (t6 = 2.27; p = 0.0637), suggesting a delayed maturation profile of the putative PV interneurons of the region. (e) Representative figures illustrating the expression of PV and PNN in the vSub of naïve and stressed rats at different time-points. Data are presented as mean ± SEM. #p < 0.05, after 1-way ANOVA and indicating developmental cell counting changes; *p < 0.05, after multiple t test and indicating stress-induced changes.
Figure 3 –
Figure 3 –. Impact of early adolescent or adult stress on the activity of pyramidal neurons in the vHipp.
(a) Adolescent stress (through PD47–54) increased the firing rate of pyramidal neurons in the vHipp 1–2 weeks (naïve group: n = 37 neurons from 10 rats, 0.62 ± 0.06 active neurons/track; stress group: n = 36 neurons from 9 rats, 0.67 ± 0.06 active neurons/track) and 5–6 weeks after the stress (naïve group: n = 26 neurons from 7 rats, 0.62 ± 0.09 active neurons/track; stress group: n = 48 neurons from 10 rats, 0.80 ± 0.08 active neurons/track). A 2-way ANOVA showed a significant effect only for condition (naïve vs. stress; F1,143 = 21.34, p < 0.0001), with no effect for age of recordings (1–2 weeks vs. 5–6 weeks post-adolescent stress, F1,143 = 0.81, p > 0.05) or interaction (F1,143 = 0.13, p > 0.05). Further analysis showed that adolescent stress increased the firing rate of pyramidal neurons in the vHipp 1–2 and 5–6 weeks post-stress compared to the respective naïve rats (Bonferroni post-hoc test, p < 0.05). (b) On the other hand, adult stress (through PD65–74) did not change the firing rate of pyramidal neurons in the vHipp with the recordings 1–2 weeks (naïve group: n = 31 neurons from 6 rats, 0.86 ± 0.13 active neurons/track; stress group: n = 29 neurons from 6 rats, 0.81 ± 0.13 active neurons/track) or 5–6 weeks post-stress (naïve group: n = 27 neurons from 6 rats, 0.75 ± 0.15 active neurons/track; stress group: n = 26 neurons from 6 rats, 0.72 ± 0.12 active neurons/track). Data are presented as mean ± SEM. *p < 0.05.
Figure 4 –
Figure 4 –. VPA treatment in the adult causes the rat to regain stress-induced DA system hyperresponsivity and increased activity of pyramidal (Pyr) neurons in the vHipp.
(a) Adult rats were treated with VPA (300 mg/kg, i.p.) for 15 days (PD60–74) and exposed to the combined stressor (daily FS through PD65–44 and 3 RS sessions at PD65, 66, and 74). Single-cell extracellular recordings of VTA DA neurons and locomotor response to acute amphetamine (0.75 mg/kg, i.p.) were evaluated 1–2 weeks post-stress. (b) VPA treatment alone did not impact the VTA DA system when tested at adulthood (PD81–88); however, it did substantially alter the impact of co-administered FS+RS (naïve+saline: n = 8 rats, 0.96 ± 0.04 active DA neurons/track; stress+saline: n = 9 rats, 0.60 ± 0.05 active DA neurons/track; naïve+VPA: n = 10 rats, 0.95 ± 0.11 active DA neurons/track; stress+VPA: n = 11 rats, 1.46 ± 0.08 active DA neurons/track). A 2-way ANOVA showed significant effect for treatment (saline vs. VPA; F1,34 = 27.49, p < 0.0001) and interaction between treatment and condition (naïve vs. stress; F1,34 = 28.96, p < 0.0001), with no effect for condition (F1,34 = 0.92, p > 0.05). Post-hoc analysis indicated that stress exposure in adult rats led to decreased VTA DA population activity that was present for 1–2 weeks after treatment (Bonferroni post-hoc test, p < 0.05 stress+saline vs. naïve+saline). However, if rats were treated with VPA, the net effect of co-administered stressors was an increase in VTA DA neuron population activity (Bonferroni post-hoc test, p < 0.05 stress+VPA vs. all groups). (c) An increased locomotor response to amphetamine was also observed in VPA-treated rats exposed to the combined stressors (n = 8 rats/group). A 2-way ANOVA showed significant effect for treatment (saline vs. VPA; F1,28 = 9.22, p = 0.005) and for condition (naïve vs. stress; F1,28 = 15.11, p = 0.0006), with no interaction (F1,28 = 2.21, p > 0.05). Post-hoc analysis indicated an increased responsivity to amphetamine in VPA-treated stressed rats (Bonferroni post-hoc test, p < 0.05 stress+VPA vs. all groups). (d) We previously found that adult stress did not change the activity of pyramidal neurons in the vHipp. However, VPA treatment changed the response to stress, but did not induce any effect by itself. VPA combined with adult stress increased the firing rate of pyramidal neurons in the vHipp 1–2 weeks post-stress (naïve+saline: n = 33 neurons from 7 rats, 0.79 ± 0.14 active neurons/track; naïve+VPA: n = 40 neurons from 8 rats, 0.83 ± 0.11 active neurons/track; stress+VPA: n = 33 neurons from 7 rats, 0.79 ± 0.12 active neurons/track; F2,103 = 3.45, p = 0.035, 1-way ANOVA followed by Bonferroni post-hoc test, p < 0.05 stress+VPA vs. all other groups). Then, we tested (e) if changes induced by VPA co-administered with FS+RS on the DA system persisted over time (5–6 weeks). (f) An increase in VTA DA neuron population activity was also present in VPA-treated rats 5–6 weeks after the adult stress (naïve+saline: n = 8 rats, 0.95 ± 0.09 active DA neurons/track; stress+VPA: n = 8 rats, 1.36 ± 0.06 active DA neurons/track; t14 = 3.59, p = 0.003). (g) In addition, VPA-treated rats also presented an increased locomotor response after amphetamine administration 5–6 weeks post-adult stress (n = 8 rats/group; t14 = 2.82, p = 0.014). (h) The increased firing rate of pyramidal neurons in the vHipp in VPA-treated animal exposed to adult stress was also present 5–6 weeks post-stress (naïve+saline: n = 30 neurons from 9 rats, 0.59 ± 0.09 active neurons/track; stress+VPA: n = 30 neurons from 9 rats, 0.57 ± 0.09 active neurons/track; t58 = 2.71, p = 0.0088). These changes observed after VPA treatment co-administered with FS+RS at adulthood are analogous to those induced by the adolescent stress. Data are presented as mean ± SEM. *p < 0.05.
Figure 5 –
Figure 5 –. Impact of VPA treatment (300 mg/kg; i.p.; PD60–74) combined with adult stress (PD65–74) on histological changes in the vHipp.
Cell counting was performed on PV interneurons to assess the effect of critical period reopening on stress vulnerability. Specifically, the ventral subiculum (vSub) was sampled at 1–2 weeks and 5–6 weeks post-stress (n = 4–6 rats/group). At each time-point, a two-way ANOVA (treatment and condition as main factors) was performed on PV+, PNN+, and PV/PNN+ cells respectively, to evaluate the effect of stress and VPA co-administration. (a) For PV+ cells, only a treatment effect was detected (F3,16 = 8.798, p = 0.0091) at 1–2 weeks post-stress. At 5–6 weeks post-stress, however, significant main effects of both condition (F1,16 = 7.674, p = 0.014) and treatment (F1,16 = 12.09; p = 0.0031), as well as a significant interaction (F1,16 = 7.684, p = 0.014), were detected. Post-hoc analysis indicated a decrease in the PV+ cell count only in stress+VPA group (Bonferroni post-hoc test, p < 0.05 stress+VPA vs. all other groups), analogous to the long-term stress response in adolescent animals. (b) Adult PNNs seemed to be stable to stress and VPA treatment, as no main effect nor interaction were detected at either 1–2 weeks or 5–6 weeks post-stress. (c) In terms of PV/PNN+ cell count, which are markers of putative mature PV interneurons, treatment effect was detected at both 1–2 weeks (F1,16 = 5.132, p = 0.0377) and 5–6 weeks (F1,16 = 6.823, p = 0.0189), but condition effect was only detectable at 5–6 weeks post-stress (F1,16 = 5.998, p = 0.0262). Moreover, a significant interaction was detected only at 5–6 weeks post-stress (F1,16 = 5.94, p = 0.0268), when the stress-VPA group displayed fewer PV+/PNN+ cells (Bonferroni post-hoc test, p < 0.05, vs. all other groups), suggestive of a relatively immature status of the PV neurons. Taken together, the data suggests that adult animals treated with VPA regained adolescent-like vulnerability to stress, evident by reduced number of PV+ and PV/PNN+ cell count at 5–6 weeks post-stress. The effect of stress did not manifest in VPA-treated rats until 5–6 weeks post-stress, a phenomenon potentially attributable to a short-term effect of VPA-treatment alone on the expression of PV. (d) Representative figures illustrating the impact of adult stress and VPA treatment on the expression of PV and PNN in the vSub. Data are presented as mean ± SEM. #p < 0.05 after 2-way ANOVA, indicating a treatment effect; *p < 0.05 after 2-way ANOVA followed by a Bonferroni post-hoc test, indicating significant changes in VPA-treated stressed rats vs. controls.
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