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Published in final edited form as: Behav Neurosci. 2023 Jun 15;137(5):281–288. doi: 10.1037/bne0000560

A single dose of ketamine enhances early life stress-induced aggression with no effect on fear memory, anxiety-like behavior, or depression-like behavior in mice

Caitlyn J Bartsch 1, Sophia Aaflaq 1, Jessica T Jacobs 1, Molly Smith 1, Fletcher Summa 1, Savannah Skinner 1, Elana Qasem 1, Rylee Thompson 1, Zheng Li 2, Jacob C Nordman 1
PMCID: PMC10694802  NIHMSID: NIHMS1903969  PMID: 37326523

Abstract

Ketamine is a dissociative anesthetic that has been shown to have antidepressant effects in humans and has been proposed as a potential treatment for mood disorders such as PTSD and aggression. However, previous studies from our lab and others have demonstrated that ketamine’s effects are highly context- and dose-dependent. In a recent study, we found that 10 mg/kg ketamine could exacerbate the effects of early life stress on excessive aggression in mice. To further investigate the effect of ketamine on moods, such as fear, anxiety, depression, and aggression, we used a mouse model of early life stress, involving chronic social isolation followed by acute traumatic stress in the form of non-contingent, unpredictable foot shock during adolescence. We find this is necessary to induce long-lasting excessive aggression in a novel environment. 7–8-week-old socially isolated mice were given IP injections of 10 mg/kg ketamine 30 minutes before being subjected to foot shock and then assessed 7 days later for changes in sociability, aggression, mobility, anxiety-like behavior, and depression-like behavior. The results show that ketamine selectively increases long-lasting aggression in mice exposed to foot shock, but does not affect mood-related behaviors or locomotion. These findings suggest that during early life stress, ketamine may exert its effects by specifically targeting aggression brain circuitry that is distinct from brain circuits responsible for non-aggressive social or emotional behaviors. Therefore, while ketamine may be a promising treatment for various mood disorders, caution should be exercised when using ketamine to treat disorders associated with early life stress.

Keywords: Aggression, early life stress, social isolation, ketamine, NMDA receptor

INTRODUCTION

PTSD, depression, anxiety, fear, and aggression are debilitating mental health conditions that can severely impact an individual’s quality of life. Although medications are available to help alleviate symptoms, they often have significant side effects, require long-term use, and may not be effective for all patients (Delbello et al., 2006; Geller et al., 2012; Pisano et al., 2019; Pringsheim, Hirsch, Gardner, & Gorman, 2015; Solmi et al., 2020).

Recently, ketamine has emerged as a potential treatment option for these conditions, particularly due to its long-lasting effects after a single dose (Burger et al., 2016; Ibrahim et al., 2012; Ma et al., 2013). However, our previous study surprisingly revealed that a single dose of ketamine increased aggression in a mouse model of early life stress-induced excessive aggression (Nordman, Bartsch, & Li, 2022). This unexpected finding prompted us to further investigate the underlying reasons for this phenomenon and evaluate the effects of ketamine on other behavioral measures in the context of early life stress.

Ketamine, a non-selective N-methyl-d-aspartate receptor (NMDAR) antagonist, has been primarily used as an anesthetic in humans and animals but has recently shown potential for managing various psychiatric disorders, including general anxiety and depression disorders (Maeng & Zarate, 2007). Ketamine also has a moderate effect treating agitation and aggression associated with PTSD (Liriano, Hatten, & Schwartz, 2019; Tran & Mierzwinski-Urban, 2019). However, conflicting reports have shown that ketamine is not effective in ameliorating PTSD-like symptoms in soldiers on the battlefield and, in some cases, can even exacerbate them (Du et al., 2022; McGhee et al., 2014; Mion, Le Masson, Granier, & Hoffmann, 2017; Schönenberg, Reichwald, Domes, Badke, & Hautzinger, 2008).

Stress also appears to be a strong factor in the effects of ketamine in mice. For example, ketamine increases aggression in sleep-deprived rats and socially isolated mice (Bartsch & Nordman, 2022; Takahashi, Morato, & Monteiro-de-Lima, 1984), but decreases aggression induced by neonatal maternal separation (Shin, Baek, Han, & Min, 2019). Within the context of traumatic stress, we show that ketamine increases aggression induced by chronic social isolation followed by acute traumatic-like stress in the form of non-contingent foot shock during adolescence (Nordman, Bartsch, & Li, 2022). We call this model early life stress.

From these findings it is clear that ketamine’s effects are highly complex, relying on factors such as dosage, context, experience, and age. Therefore, a more thorough understanding of the behavioral consequences of a single dose of ketamine under chronic or acute stress during adolescence will be essential in determining its proper clinical use.

In the current study, we aimed to determine why a single dose of ketamine increased aggression when administered during the acute traumatic stress-like component of our early life stress model by examining its impact on other psycho-behavioral features (Nordman et al., 2022; Nordman, Ma, Gu, et al., 2020; Nordman, Ma, & Li, 2020). This model produces long-lasting fear memory, anxiety-like behavior, and depression-like behavior in mice. We systemically injected ketamine before foot shock in our early life stress paradigm and measured fear memory, locomotion, anxiety-like behavior, and depression-like behavior 7 days later.

Our results confirmed our previous finding that ketamine increases early life stress-induced aggression when administered during acute foot shock. However, we found no effects of ketamine on long-lasting fear memory, mobility, anxiety-like behavior, or depression-like behavior in our early life stress model. These results indicate that ketamine selectively affects early life stress-induced aggression without improving other measures of fear memory, anxiety-like behavior, or depression-like behavior. Findings from this study may lead to a better understanding of the therapeutic potential and limitations of ketamine while demonstrating the need for greater care when prescribing ketamine to treat mood disorders.

METHODS AND MATERIALS

Animals

All animal protocols were approved by the Animal Care and Use Committee of Southern Illinois University School of Medicine and the National Institute of Mental Health at the National Institutes of Health. All C57BL/6 mice used in this study were purchased from Charles River Laboratories and housed under a reverse 12-hour light (9 pm-9 am)/dark (9 am-9 pm) cycle with ad libitum access to water and food. Starting at 3–4 weeks of age, mice were either group-housed or socially isolated for 4 weeks before testing. Smaller, submissive target mice were group-housed with littermates for Fig. 2. Male mice were used for all experiments.

Fig. 2: Ketamine enhances early life stress-induced aggression without effecting non-aggressive social interaction.

Fig. 2:

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(A) Experimental setup. (B-C) Aggressive (B) and non-aggressive (C) behavior during the aggression test. Mice that were delivered early life stress (ELS) were administered vehicle or 10 mg/kg ketamine (Ket) before foot shock. Data are mean +/− SEM. *p,0.05.

Early-life stress induction and drug injections

3–4-week-old male C57BL/6 mice were socially isolated for 4 weeks in a reverse light cycle as described above. Mice were then transferred from their housing room to a behavior room shielded from light and then allowed to acclimate for 1 hour before being placed into a white light-illuminated fear conditioning chamber within a sound-attenuating cubicle (Med Associates). After a 3 min exploration period, 15 non-contingent electric foot shocks (0.4 mA, 1 s in duration) were administered through an electrified grate at random intervals of 240 – 480 s over 90 min (Nordman et al., 2022; Nordman, Ma, Gu, et al., 2020; Nordman, Ma, & Li, 2020) (summarized in Fig. 1). For pharmacology experiments, mice were injected with saline or drugs 30 min before foot shock. Mice were then transferred from their home cages by gently picking up the animals by the base of their tails, placing them into a soup cup, and then putting them inside the fear conditioning chamber. Care was taken to avoid degloving. Mice were returned to their home cages using the same method.

Fig. 1: Experimental method used in this study.

Fig. 1:

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3–4-week-old mice were socially isolated for 4 weeks. 10 mg/kg ketamine or vehicle was injected 30 minutes before 15 non-contingent, semi-random foot shocks (1 sec, 0.4 mA) over 90 min. Behavior was assessed 7 days later.

Pharmacology

Ketamine (10 mg/kg, Tocris) (Newman et al., 2012; Newman et al., 2018; Nordman et al., 2022) was dissolved in 0.9% saline. 7–8-week-old mice were injected intraperitoneally (IP) using a 27-gauge needle 30 min before being placed in the fear conditioning chamber. 0.9% saline was used as a vehicle control.

Behavioral testing

All tests, except for short-term mobility, were performed 7 days after early life stress induction or in control mice that were group-housed for 4 weeks and then placed in the fear conditioning chamber for 90 min without receiving foot shocks (no early life stress (no ELS)), as previously described (Nordman et al., 2022; Nordman, Ma, Gu, et al., 2020; Nordman, Ma, & Li, 2020). This model shows that the combination of chronic and acute stress are necessary for long-lasting aggression in a novel enviornment. All mice were transferred to the behavioral testing room at least 1 hour before testing to acclimate. Each test was performed on a separate group of mice.

Aggression test.

Mice were placed in a high-walled novel cage and allowed to acclimate for 20 min before introducing a younger, group-housed conspecific (Fig. 2A). Both mice were allowed to freely interact for 10 min while their behavior was captured with a video camera. The test was prematurely terminated and not analyzed if excessive tissue damage occurred. Videos of aggression tests were reviewed and hand scored by a researcher unaware of the experimental conditions. Inter-observer reliability was assessed and confirmed for all researchers using a sample data set. Aggressive behaviors such as attacks to the rear, attacks to the front/face, boxing, chasing, and wrestling were identified as reported (Blanchard & Blanchard, 1977; Nordman & Li, 2020; Nordman, Ma, Gu, et al., 2020; Nordman, Ma, & Li, 2020). Non-aggressive social behavior was defined as any interaction in which experimental mice were within 1 cm of the conspecific and displaying characteristic signs of non-aggressive social behavior such as anogenital sniffing, investigation, and flank rubbing.

Sociability test.

Mice were placed into a 49 × 49 cm arena with two inverted wire cups: one empty and the other containing an unfamiliar conspecific (Fig. 3A). Injected mice were allowed to freely investigate the arena for 30 min. All experiments were conducted under light with a luminescence level of 20 lux at the bottom of the arena. Social interaction was analyzed using TopScan software (CleverSys) and scored as the ratio of the number and duration of time spent within 5 cm of the cup containing the animal over the empty cup.

Fig. 3: Ketamine does not affect sociability after early life stress.

Fig. 3:

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(A) Experimental setup. (B-C) Ratio of the number of (B) or time spent (C) interacting with the cup containing a mouse to the time interacting with the empty cup (SI score) during the social interaction test. Data are mean +/− SEM.

Mobility test.

Mice were placed into a 49 × 49 cm open field arena and allowed to roam freely for 30 min (Fig. 4A) immediately after drug injection, immediately after drug injection and foot shock, or 7 days after drug injection and foot shock. Mobility was measured as distance traveled, which was analyzed using TopScan software (CleverSystems).

Fig. 4: Ketamine does not affect mobility immediately after injection or after early life stress.

Fig. 4:

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(A) Experimental setup. (B-D) Distance travelled during the open field test after injection (B), immediately after early life stress (ELS) (C), or 7 days after ELS (D). Data are mean +/− SEM.

Contextual fear memory test.

1 day after early life stress induction, mice were placed into a fear conditioning box modified with white plastic walls, no ambient light, and a background odor of 1% acetic acid (Context B) (Fig. 5A). Mice were left to freely roam within the chamber for 192 s before a single 1 s, 0.4 mA shock was delivered via an electrified grate, and were removed from the chamber 32 s after foot shock. The following day, mice were placed into Context B for 8 min 32 s and monitored for freezing behavior. Freezing behavior was defined as an absence of all movement, excluding respiration, and was analyzed with Video Freeze software (Med Associates).

Fig. 5: Ketamine does not affect early life stress-induced fear memory.

Fig. 5:

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(A) Experimental setup. (B) Analysis of freezing behavior in Context B. Data are mean +/− SEM.

Light/dark box.

Mice were placed in the light compartment of a light/dark box with dimensions of 46 cm x 27 cm x 30 cm, where one-third of the box was dark and two-thirds were illuminated with 390 lux light (Takao & Miyakawa, 2006) (Fig. 6A). Mice were then allowed to freely explore the test box for 11 min. The box was cleaned with 30% ethanol and then water between runs. The test was recorded using a ceiling-mounted camera and then analyzed using TopScan software (CleverSystems).

Fig. 6: Ketamine does not affect early life stress-induced anxiety-like behavior.

Fig. 6:

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(A) Experimental setup. (B) Time spent in the light compartment during the light/dark box test. Data are mean +/− SEM.

Sucrose preference test.

Mice were placed in a new cage and given access to two bottles, one containing a 1% sucrose solution and the other containing plain drinking water (Fig. 7A). During the 72-hour test period the mice were allowed to freely choose between the two bottles without any food or water deprivation. To ensure that side preference did not affect the mice’s drinking behavior, the position of the bottles was switched every 24 hours. The intake of each liquid and total fluid consumption was measured by weighing the bottles before and after the mice had access to them during both the habituation and test phases. The sucrose preference was calculated as the percentage of sucrose solution consumed compared to the total amount of liquid consumed during the 72-hour test period (sucrose solution intake/total intake x 100).

Fig. 7: Early life stress increases depression-like behavior that is unaffected by ketamine.

Fig. 7:

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(A) Experimental setup. (B-C) Sucrose preference in non-stressed mice (no ELS) and mice exposed to early life stress (ELS) injected with ketamine or vehicle. Sucrose preference (preference score) was calculated as percentage of 1% sucrose solution consumed compared to the total amount of liquid consumed per day (B) or averaged over all 3 days (C). Data are mean +/− SEM. **p < 0.01, ***p < 0.001.

Statistical analysis

All data were presented as mean ± SEM. SigmaPlot software was used for statistical analysis. One-way ANOVAs were used for all experiments, comparing no early life stress (no ELS) to ketamine or vehicle-treated mice. Boneforroni post-hoc tests were used for multiple comparisons to identify groups that were significantly different. p < 0.05 was considered significant and all tests were two-tailed.

Transparency and Openness

All manipulations and measures are reported in the study. All data and research materials are available upon request. Data was analyzed using SigmaPlot. This study’s design and its analysis were not pre-registered.

RESULTS

Ketamine enhances aggression, but not non-aggressive social behavior, after early life stress.

We began by confirming our previous findings that ketamine increased early life stress-induced aggression without affecting non-aggressive social behavior (Nordman et al., 2022). As described in the methods, mice were socially isolated for 4 weeks starting at 3–4 weeks of age. IP injections of 10 mg/kg ketamine or vehicle were then injected into the mice 30 minutes before foot shock. For controls, we used mice that were group-housed for 4 weeks and then placed in the shock box for 90 min without receiving foot shocks (no early life stress (no ELS)). 10 mg/kg was used because it was effective at increasing aggression in our previous study (Nordman et al., 2022). Aggression was measured 7 days later. Consistent with our previous findings, ketamine significantly enhanced aggression compared to vehicle or no ELS (F(2,13) = 10.807, p = 0.0017; no ELS vs vehicle, p = 0.41; no ELS vs ketamine, p = 0.0014; vehicle vs ketamine, p = 0.043) (Fig. 2A–B). No significant differences were observed for non-aggressive social behavior (F(2,13) = 0.136, p = 0.874) (Fig. 2C).

We next measured sociability in a separate group of mice using the sociability test (Fig. 3A). There were no significant differences in the ratio of time spent by the cup containing the animal vs. the time spent by the empty cup between no ELS and ketamine and vehicle-treated groups 7 days after early life stress (F(2,6) = 0.415, p = 0.678 for # of times; F(2,6) = 0.199, p = 0.825 for duration of time) (Fig. 3B–C).

These findings confirm that ketamine enhances aggression without affecting non-aggressive social interaction.

Ketamine does not affect mobility, fear, anxiety-like behavior, or depression-like behavior.

Ketamine is a medication commonly used as an anesthetic in humans and animals, which can affect mobility in mice (Fitzgerald, Yen, & Watson, 2019). To assess if ketamine affects short-term mobility, we injected ketamine or vehicle into socially isolated mice and then tested them for mobility in an open field 30 min later. No ELS was used as a control. We observed no significant difference between no ELS, ketamine-treated, and vehicle-treated mice (p = 0.847) (Fig. 4A–B). We also tested mobility in separate groups of mice immediately after foot shock. Again, we observed no significant difference between no ELS, ketamine-treated, and vehicle-treated mice (F(2,7) = 0.385, p = 0.694) (Fig. 4C).

Finally, we tested if ketamine affected long-term mobility in our early life stress model. Ketamine or vehicle were injected 30 min before foot shock and no ELS was used as a control. Mobility was measured in an open field 7 days later. There was no difference in mobility between no ELS, ketamine-treated, or vehicle-treated animals (F(2,6) = 0.469, p = 0.647) (Fig. 4D), as above.

Ketamine has been successful in treating PTSD in humans and ameliorating the effects of foot shock, a model of traumatic stress, in mice (Liriano, Hatten, & Schwartz, 2019; Shin et al., 2019). Our early life stress model increases freezing behavior in the Context B test (Nordman, Ma, Gu, et al., 2020; Nordman, Ma, & Li, 2020). To assess if ketamine can suppress fear behavior in mice exposed to our early life stress model, we injected ketamine or vehicle 30 min before foot shock (Context A) and then measured freezing behavior in a novel environment (Context B) 7 days later. We observed a significant group effect (F(2,13) = 8.643, p = 0.004) and significant difference between no ELS and injected mice (no ELS vs vehicle, p = 0.005; no ELS vs ketamine, p = 0.020), but observed no difference between vehicle and ketamine-injected mice (p = 0.391) (Fig. 5).

Ketamine has been shown to have anxiolytic (anxiety-reducing) and antidepressant effects in humans and mice (da Silva et al., 2010; Ibrahim et al., 2012; Maeng & Zarate, 2007). To measure if ketamine suppresses anxiety-like behavior 7 days after early life stress, we used the light/dark test (Nordman, Ma, & Li, 2020). We observed a significant group effect in the duration of time spent in the light compartment (F(2,6) = 9.140, p = 0.020) and between no ELS and injected mice (no ELS vs vehicle, p = 0.023; no ELS vs ketamine, p = 0.027), but no significant differences between ketamine and vehicle-treated mice (p = 0.830) (Fig. 6).

Finally, we measured if ketamine suppresses depression-like behavior 7 days after early life stress using the sucrose preference test, a standard and reliable measure of depression-like behavior in mice (Liu et al., 2018). This was conducted 7 days after the mobility experiments in Fig. 4C above. We observed a significant group effect for days 1–3 (F(2,12) = 13.14, p = 0.001) and decrease in sucrose preference after early life stress (p = 0.017 for no ELS vs. vehicle; p = 0.001 for no ELS vs ketamine) (Fig. 7). However, no difference was observed between ketamine and vehicle-treated mice exposed to early life stress (p = 0.411).

These findings suggest that ketamine does not suppress mobility, fear memory, anxiety-like behavior, and depression-like behavior in mice exposed to early life stress.

DISCUSSION

In this study, we investigated the effect of a single dose of ketamine during early life stress on mood and behavior. Previous findings from our lab showed that early life stress promotes long-lasting aggression, fear, anxiety-like behavior, and depression-like behavior in mice (Nordman et al., 2022; Nordman, Ma, Gu, et al., 2020; Nordman, Ma, & Li, 2020). The NMDAR-antagonists MK-801 and memantine suppressed the aggression increase, but contrary to our expectations, a single dose of ketamine enhanced it (Nordman et al., 2022). We confirmed the finding that a single dose of ketamine enhances early life stress-induced aggression but did not observe an effect on non-aggressive social behavior, mobility, fear, anxiety-like behavior, and depression-like behavior. These results indicate that ketamine may be ineffective at treating mood disorders while exacerbating long-lasting aggression associated with early life stress.

Ketamine has mixed effects on aggression, anxiety, depression, and fear in humans and rodents

While single-dose ketamine is garnering attention as a potential pharmacological treatment for psychological disorders, studies in mice show vast differences in its effects on depression, aggression, anxiety, and fear when experiencing stress. For example, single-dose ketamine decreases aggression induced by neonatal maternal separation (Shin et al., 2019) but increases aggression in REM sleep-deprived and food-deprived rats and socially isolated mice (Nordman et al., 2022; Takahashi et al., 1984), indicating important age and sex-specific effects that should be considered in future experiments.

In fear memory, a single dose of ketamine can alleviate generalized fear and enhance fear discrimination and extinction in mice (Asim et al., 2020; Ryan, Tse, Huang, Yang, & Lee, 2022). However, other studies have found no improvement in fear memory following ketamine treatment (Choi, Berman, Zhang, Spencer, & Radford, 2020; Juven-Wetzler et al., 2014). Timing of administration is an important consideration, with one study showing that ketamine can only suppress fear memory when injected 1 week prior to contextual fear conditioning (McGowan et al., 2017).

A single dose of ketamine can produce long-lasting antidepressant effects in mice exposed to chronic mild stress (Ma et al., 2013), but other studies have shown no effect (Fitzgerald et al., 2019). Ketamine yields largely negative or neutral results in tests that measure anxiety-like behavior with wistar kyoto rats, appearing to be an exception (da Silva et al., 2010; Fortress, Smith, & Pang, 2018; Loss, Cordova, & de Oliveira, 2012; Pitsikas, Georgiadou, Delis, & Antoniou, 2019; Silote et al., 2020).

While it is important to note that many variables existed across these studies, the varied effects of ketamine on mood are intriguing and highlight the need for more research.

Contrasting effects of ketamine with different NMDAR antagonists

NMDARs are members of the ionotropic glutamate binding receptor family (Willard & Koochekpour, 2013). Glutamate is essential in processes of learning, memory, and plasticity, which are key components in the formation of traumatic memories associated with PTSD. Ketamine, memantine, and MK-801 are non-competitive NMDAR antagonists with similar drug profiles. Despite these similarities, ketamine has shown opposing effects on aggression from memantine and MK-801, indicating there are differences in these drugs that are not fully understood (Bartsch & Nordman, 2022; Nordman, 2021).

One difference is that memantine may bind more readily to extrasynaptic NMDARs than ketamine, but findings are mixed (Emnett et al., 2013; Leveille et al., 2008; Okamoto et al., 2009; Wroge, Hogins, Eisenman, & Mennerick, 2012). Possibly the most important difference between ketamine and other NMDAR antagonists is selectivity. While ketamine acts primarily on NMDARs, it also binds muscarinic, nicotinic, monoaminergic, and opioid receptors, suggesting its effects on mood may not be entirely glutamate-dependent (Hirota & Lambert, 1996).

Finally, we previously showed that attack experience and early life stress heighten aggression by synaptically potentiating glutamatergic synapses within a medial amygdala circuit (Nordman, Ma, Gu, et al., 2020; Nordman, Ma, & Li, 2020). MK-801 suppresses aggression priming and synaptic potentiation at these synapses, strongly suggesting early life stress-induced aggression is NMDAR-dependent.

While ketamine is a known inhibitor of potentiation, it has been shown to enhance potentiation at hippocampal synapses of socially defeated mice (Yang, Ju, Zhang, & Sun, 2018) and disinhibit excitatory signaling that increases synaptic activity in the PFC (Homayoun & Moghaddam, 2007). A similar mechanism could be operating in MeA pathways, whereby ketamine disinhibits excitatory signaling at MeA synapses, leading to further potentiation that enhances aggression after early life stress. We intend to examine these possibilities in future studies.

Concluding remarks

Adverse childhood experiences (ACEs), including physical, sexual, or emotional abuse or neglect, can lead to severe mood disorders such as depression, anxiety, and pathological aggression (McKinney, Caetano, Ramisetty-Mikler, & Nelson, 2009; Whitfield, Anda, Dube, & Felitti, 2003). Prolonged stress and trauma associated with ACEs often exacerbate the symptoms of these conditions, resulting in persistent feelings of hopelessness and worry or uncontrolled bouts of anger and violence. Unfortunately, traditional therapies or medications aimed at treating the negative outcomes of ACEs are largely ineffective.

Ketamine has emerged as a promising treatment for depression, but its efficacy in addressing aggression, anxiety, or symptoms related to ACEs is not well understood. Our study in a mouse model of early life stress found that, contrary to expectations, ketamine worsens aggression while having minimal impact on anxiety, depression, and fear behavior. These results highlight the need for further research on ketamine and caution when prescribing it to treat psychiatric conditions related to ACEs. Our laboratory will continue to investigate these important questions in the future. Furthermore, given that the effects of ketamine is highly dependent on a prior history of traumatic stress, a more thorough medical evaluation and psychiatric assessment be given before prescribing NMDAR drugs to avoid possible adverse effects on aggression.

Acknowledgments:

We would like to acknowledge Craig Logan and Jennifer Davis for their assistance with this work. This work was supported by a Research Seed Grant from Southern Illinois University School of Medicine to J.C.N., a Postdoctoral Research Associate Training (PRAT) Program Award from National Institute of General Medical Sciences to J.C.N., a Research-Enriched Academic Challenge (REACH) award to C.J.B. and S.S., and a 1Z1AMH002881 from the National Institute of Mental Health Intramural Research Program to Z.L.

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