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Published in final edited form as: Trends Neurosci. 2025 Jul 16;48(8):582–593. doi: 10.1016/j.tins.2025.06.004

Untangling the multifaceted VTA responses to stress

Urszula Skupio 1,2, Alexander Z Harris 1,2,*, Abigail M Polter 3,*
PMCID: PMC12308838  NIHMSID: NIHMS2098261  PMID: 40675841

Abstract

Stress has profound impacts on the ventral tegmental area (VTA). However, the complex and opposing effects of stress on the VTA have limited the ability to reach a clear understanding of how adaptation of the VTA can drive behavior following stress. In this review, we provide an overview of VTA responses to acute and chronic stress, with a primary focus on studies in mice and rats. We propose that divergent responses to stress arise from the heterogeneity of VTA neurons, the multi-dimensional nature of stress, and interactive effects between cumulative stressors. We suggest that the robust and varied plasticity of the VTA in response to stress indicates a role for the VTA as an integrator of homeostatic and affective information during stress to drive flexible and nuanced adjustments in behavioral adaptation.

Keywords: dopamine, plasticity, reward circuitry, acute stress, chronic stress

Diverse VTA networks in stress adaptation

The ventral tegmental area (VTA) has emerged as a critical mediator of both immediate responses and long-term adaptations to acute and chronic stress. Neurons in this brain region are highly responsive to stressful stimuli and regulate an array of behaviors related to reward, avoidance, motivation and learning [1,2]. Making sense of the role of the VTA in responding and adapting to stress requires synthesizing complex, sometimes contradictory data. The relationship between activity of VTA neurons and stress depends heavily on the type, duration, and intensity of stress, and different stress paradigms can have similar behavioral effects while resulting in opposing functional alterations to VTA circuitry. These variations in responses between paradigms and individuals can be a valuable tool to explore how the VTA adapts to experience and modulates behavior in response to ongoing challenges.

The VTA contains a remarkable heterogeneity of neurons, including dopaminergic, GABAergic, and glutamatergic populations, many of which support release of multiple transmitters (reviewed, [3–8]) (Figure 1). Synaptic input onto VTA neurons from both local and distal sources forms a hub linking neuronal networks involved in processing of emotional and salient information with circuits underlying executive functioning [9,10]. Neurons that release dopamine constitute the majority of neurons in the VTA (~60% in rodents); a subset of these cells also co-releases GABA and/or glutamate [6,11,12]. VTA doapmine neurons project to limbic and cortical brain regions, often in discrete pathways with minimal overlap or collateralization [10,13]. The primary dopaminergic outputs of the VTA include the medial and lateral nucleus accumbens (NAc), medial prefrontal cortex (mPFC) and the amygdala [14,15]. These dopaminergic projections play a role in a wide range of behaviors in both laboratory and naturalistic settings. Dopamine neurons are particularly important for effort- and value-based decision-making, and specifically for calculating the expected values of behaviorally relevant stimuli and outcomes in goal-directed behavior [9,16]. They play additional roles in a wide range of functions, including social behavior [17,18], cognition [19], monitoring of internal states [20], perception of time [21], and titrating force of movement [22].

Figure 1. Major projections and behavioral functions of VTA dopamine, GABA and glutamate neurons in rodents.

Figure 1.

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Color-coded dots adjacent to each brain structure indicate the projections: dopamine (yellow), GABA (red) and glutamate (blue) neurons originating from the VTA. Smaller dots associated with listed behavioral functions denote the established involvement of these specific VTA neuronal populations in the respective behaviors. Behavior functions listed without a colored dot next to them indicate behaviors that have been associated with the respective projection, but where the cell type of the projecting neurons is unclear or not yet identified. Abbreviations: DA, dopamine; Glu, Glutamate; PFC, prefrontal cortex; med. NAc, medial nucleus accumbens; lat. Nac, lateral nucleus accumbens, VP, ventral pallidum; HIP, hippocampus; LHb, lateral habenula; AMY, amygdala; DR, dorsal raphe; VTA, ventral tegmental area.

VTA GABAergic and glutamatergic neurons form local connections with dopaminergic and non-dopaminergic neurons and shape behavior by altering excitability of dopaminergic neurons [23,24]. However, these neurons also send projections to distal brain regions, and through them can exert dopamine-independent effects on behavior. Some of these projections occur in parallel with dopaminergic neurons to regions such as the nucleus accumbens, while others project to regions that receive little dopaminergic input such as the lateral habenula [25]. Both GABA and glutamatergic neurons influence reward consumption, reinforcement and anticipation, motivation, stress responses and sleep [3,6,8,26–30]. While there is significant heterogeneity among both VTA GABAergic and VTA glutamatergic neurons, the lack of consensus on the molecular and physiological organizations of subtypes of these neurons remains a significant barrier to understanding their functional roles.

Here, we review the role of VTA dopaminergic, GABAergic, and glutamatergic neurons in acute and chronic stress, and subsequent behavioral changes. We provide an overview of recent literature across rat and mouse models, including potential explanations for heterogeneity in VTA adaptations between models of both acute and chronic stress. We argue that these differences point to a role of the VTA as an integration point for homeostatic and affective signals, to direct future behavior based on demands and features of stress. Finally, we highlight future directions that will be beneficial for deepening our understanding of the complex roles of VTA neurons in stress.

Effects of acute stress on the VTA

In rodent models of stress, acute stress encompasses a wide range of experiences, from momentary stimuli such as a single footshock, to single sessions of stressors such as restraint or repeated footshock (Box 1). In rats, a subset of dopaminergic neurons was shown to fire in response to footshock, while others are inhibited during footshock and fire at the offset [31]. Other studies have shown that a single session of multiple intermittent foot- or tail- shock leads to an increase in dopamine release in the rat nucleus accumbens [32,33] and prefrontal cortex [33]. VTA dopamine neurons also play a role in the extinction of footshock-associated fear memories [34–36]. Activating VTA dopamine neurons reduces persistent fear memory in rats [34]. In mice, dopamine projections to the basolateral amygdala (BLA) were shown to bidirectionally regulate extinction by both suppressing fear responses and promoting extinction memory [35,36]. Restraint stress causes some dopamine neurons to increase their firing rates and release dopamine in the nucleus accumbens [37,38], while restraint leads to silencing of dopamine neurons [39]. Release from restraint also increases dopamine levels in both mice and rats [38,40]. Pre-stress activity rates may influence this heterogeneity of responses, as restraint stress enhances burst firing in neurons with high baseline burst rates, but minimally affects activity in neurons with low baseline bursting [37]. A similar pattern was observed during a single social defeat session in rats, which showed an increase in burst firing in neurons with higher burst rates during aggressive confrontations [41]. This is also seen in mice, where a single social defeat session activates a genetically trapped ensemble of dopaminergic, glutamatergic, and GABAergic neurons, which showed higher excitability in ex vivo slices [42]. In vivo silencing of the same genetically trapped ensemble prevented social avoidance following social defeat [43]. Some projections respond non-selectively to stimuli across valence; for example, using calcium imaging, dopamine neuron terminals in the mouse ventral NAc were shown to be activated by both aversive and rewarding stimuli [7,44]. This suggests that dopaminergic projections to some portions of the nucleus accumbens encode the motivational salience of stress rather than valence [45,46].

Box 1: Rodent models of stress.

Commonly used stress paradigms in adult rodents include physical, social, or environmental stressors. These can be used alone or in combination, acutely or chronically, and yield complex effects across a variety of behavioral domains. Below we present a summary of commonly used approaches and their behavioral outcomes (for reviews see [118–121]).

  1. Physical stressors. Physical stressors, such as electric shock, restraint/immobilization, and forced swimming are often used due to their procedural simplicity, reproducibility and adjustable intensity. Both acute and chronic exposure to these stressors produces a range of behavioral effects in rodents. Among the most commonly observed are anhedonic behaviors, manifested by a decrease in sucrose preference; changes in motivation measured by progressive ratio task and effort based tasks; alterations in learning and memory assessed using the Morris water maze and novel object recognition tests; increased anxiety-like behaviors, measured as time spent in the open arms of elevated plus maze; and passive stress coping strategies measured as increased immobility in forced swim and tail suspension tests [118,121]. Although physical stressors offer reduced variability in behavioral outcomes, potentially beneficial in certain experimental designs, they may not adequately capture individual sensitivity/resilience to stress. Additionally, physical stressors might provoke nociceptive and inflammatory responses [122], potentially confounding the interpretation of the results.

  2. Social stressors. Approaches using social stressors include social defeat and social isolation. Rodents repeatedly subjected to unavoidable aggression often exhibit long-lasting social avoidance, decrease in social preference, as well as reduced sucrose preference [73,118]. It has also been shown to enhance self-administration of addictive substances like alcohol and cocaine [123]. Social defeat can be successfully used in both males and females [74] and is often used to study individual resilience to stress, as some mice subjected to the same stress fail to develop these behavioral alterations [124]. Chronic social isolation stress increases aggressive behaviors during social interaction, reduces social novelty preference and increases anxiety-like behaviors in the open field test [118].

  3. Environmental stressors. Alterations in environmental factors, like sudden changes in temperature, noise and lighting conditions or exposure to predator odors can significantly impact stress response systems in rodents. These approaches are used to model the chronic low-grade stress that people with depression report. The commonly used paradigm of chronic unpredictable stress (CUS) mixes environmental and physical stressors of mild to moderate intensity over extended periods of time to elicit long-lasting reductions in sucrose preference, increased immobility in the forced swim test and altered performance in anxiety-related tasks, such as elevated plus maze, indicating heightened anxiety levels [118]. CUS can also result in social avoidance behaviors during social interaction [118].

Non-dopaminergic neurons in the VTA also respond robustly to stress. In mice, footshocks or air puffs increase VTA GABAergic neuron activity [47,48], leading to inhibition of VTA dopamine neurons through GABAA receptor-mediated transmission [23,48]. Stimulation of VTA GABA neurons causes conditioned place aversion and disrupts reward consumption [23,48], while inhibition of these cells is rewarding and reinforcing [49]. During acute restraint, VTA GABA neurons drive rhythmic 4 Hz oscillations in the NAc, leading to reduction in reward-seeking behaviors in mice [39]. Inhibition of VTA GABA neurons during stress ameliorates these deficits in reward seeking, whereas artificially inducing stress-like activity in NAc-projecting VTA GABA neurons in unstressed mice leads to diminished reward seeking [39]. VTA GABAergic that co-express somatostatin are activated by acute social defeat stress and drive subsequent restorative sleep that reduces stress in mice [50]. VTA glutamatergic neurons also show an increase in activity in response to foot- or tail- shock, potentially encoding aversive signals through projections to the dorsal hippocampus and/or zona incerta [27,51–53]. Recent studies have identified VTA glutamatergic neurons as key regulators of fear memory generalization and anxiety-like behaviors. Specifically, activation of VTA glutamatergic neurons enhances footshock-evoked freezing, while their inhibition reduces fear responses [52], and decreases escape behavior to looming stimulus in mice [27]. Interestingly, mice will spend less time but make more entries into a chamber paired with optogenetic stimulation of VTA glutamate neurons and will nose-poke for stimulation of these cells neurons, but prefer a brief duration of stimulation [54]. This suggests that while a brief activation of VTA glutamate neurons is reinforcing, prolonged activation becomes neutral or aversive.

Acute stress also leads to alterations in VTA function that outlast the stressor itself. These are often expressed as plasticity of synaptic inputs or intrinsic properties of neurons. Acute swim stress increases the AMPA/NMDA ratio of excitatory synapses onto VTA dopamine neurons [55,56], and blocks potentiation of GABAergic synapses onto dopamine neurons [56–58] for several days after stress, leading to prolonged changes in VTA function. A single session of unpredictable footshock increases the excitability of VTA GABAergic neurons for at least 24 hours after stress [59]. Similarly, restraint causes a shift in the chloride reversal potential in VTA GABAergic neurons, leading to increased excitability of VTA GABA neurons and enhanced inhibition of VTA dopamine neurons for at least a day after stress [60]. These studies reveal that the response of the VTA to acute stress can be prolonged, and in some cases multi-phasic. This is in line with a role for the VTA in orchestrating behavioral responses that are essential for immediate aftermath, recovery, and avoidance of future stressors.

Effects of chronic stress on the VTA

Chronic stress alters VTA function, and numerous studies have causally linked these functional alterations to behavioral sequelae of chronic stress. In the chronic unpredictable stress (CUS) paradigm, rodents are subjected to a series of randomized stressors involving transient changes in social or physical environment over weeks or months [61] (Box 1), leading to reduced sucrose preference and increased passive coping [62]. CUS decreases population activity and burst activity of VTA dopaminergic neurons in anesthetized male and female rats [63–67] and mice [68]. This decrease in firing rate is recapitulated in recordings from dopaminergic neurons in ex vivo slices from mice; however, some studies show this effect in retrogradely labeled projections to the nucleus accumbens lateral shell [68], while others show a preferential decrease in retrogradely labeled projections to the mPFC [69,70]. Several potential mechanisms for these changes have been identified, including activity in distal brain regions [63,64], as well as synaptic and intrinsic changes within the VTA [66,68,70,71].

Suppression of dopaminergic activity is causally linked to the behavioral sequelae of CUS. Phasic optogenetic stimulation of dopaminergic neurons during post-stress behavioral testing normalizes active coping in the tail suspension test and reverses sucrose preference deficits in male CUS rats [67], while in female rats exposed to CUS, chronic phasic optogenetic stimulation of dopaminergic axons during stress prevented stress-induced deficits in both the elevated plus maze and open space swimming test [72]. In mice, activation of PFC-projecting dopaminergic neurons increases both active coping in the tail suspension test and sucrose preference following CUS [70], while viral normalization of downregulated potassium channels in the VTA prevented CUS-induced deficits in body weight, sucrose preference, novelty suppressed feeding, and the forced swim test [68]. Taken together, although there are some discrepancies in the details, there seems to be conclusive evidence across species and measurements that CUS leads to diminishment of dopaminergic function that contributes to behavioral changes after stress.

Another chronic stress model used in rodents is that of chronic social defeat stress (CSDS) and associated variations [73–75] (Box 1). In this paradigm, mice or rats are subjected to brief physical defeat by an aggressor followed by 24 hours of sensory contact with the same animal. This procedure is repeated with a new aggressor daily over 10–15 days. Following CSDS, mice exhibit social avoidance and decreased sucrose preference, among other behavioral alterations [76]. In C57BL/6 male mice, CSDS induces a high rate of variability in behavioral responses, allowing separation of “susceptible” and “resilient” mice and investigation of mechanisms of individual differences [76]. CSDS and associated paradigms increase the activity of the VTA dopaminergic system, particularly in susceptible animals [76–83]. This is evident from both ex vivo studies that show an increase in the tonic firing rate of dopaminergic neurons of male [76–78] and female mice [84] and in vivo electrophysiological studies in anesthetized animals that show an increase in both tonic and phasic activity in male mice [79–81,83,85]. In male mice, normalization of dopaminergic firing rate reverses susceptibility to post-CSDS behavioral changes [76,77,82]. The relationship between dopaminergic activity and susceptibility to CSDS is specific to projection target and behavioral test. Dopaminergic neurons projecting to the nucleus accumbens have an elevated ex vivo firing rate following CSDS, and inhibition of this pathway in susceptible mice reverses deficits in social avoidance and sucrose preference [77]. In contrast, activity of PFC-projecting dopaminergic neurons is decreased by CSDS, and inhibition of this pathway increases susceptibility to subthreshold defeat [77]. Similarly, amygdala-projecting dopaminergic neurons exhibit reduced activity following CSDS, and enhancing their activity prevents deficits in approach-avoidance behavior in the open field and elevated plus maze tests, but not social interaction or sucrose preference [86].

Studies have revealed a number of mechanistic targets that may play a role in modification of VTA dopaminergic neurons. These include potassium channels that modulate both regulation of dopaminergic firing and susceptibility to CSDS [78,81,87], as well as projections to the VTA from the ventral pallidum [88]. Both cholinergic and noradrenergic projections to the VTA play a role in susceptibility to CSDS in mice [79,84,85,89,90], suggesting that responses to social defeat may be controlled by neuromodulatory inputs working in parallel to shape activity of the VTA in response to stress.

Reconciling divergent VTA responses to stress

Distinct adaptations from distinct stressors

It is clear that some of the heterogeneity of stress-induced responses in the VTA can be ascribed to different sub-populations of dopaminergic neurons. The bulk of the literature on effects of stress on the VTA has relied on rough estimation of broad dopaminergic, glutamatergic, and GABAergic populations from electrophysiological and neurochemical properties. However, the past decade has seen an increased focus on differentiating dopaminergic neurons projecting to specific regions; this approach has revealed a high degree of heterogeneity of these populations and their responses in different behavioral contexts. Differences between these populations are particularly relevant for acute stress, as neurons with differing locations within the VTA and projection targets exhibit different responses to aversive stimuli. There are likely to be additional substructures that provide heterogeneity within or across projections. Other factors such as responses to neuromodulators, intrinsic excitability or firing pattern may also drive heterogeneous responses. For instance, in the VTA, restraint stress leads to increased bursting specifically of cells with a high baseline burst rate [37]. While this could be indicative of different baseline bursting among different projections, it could also indicate preferential activation of already active cells, similar to the allocation of highly active neurons to ensembles, as is the case for memory traces in the hippocampus [91].

Chronic stress paradigms also exhibit projection-specific alterations in dopaminergic firing, but within a given projection, distinct protocols elicit different changes, suggesting this is not the sole driver of heterogeneous responses. To understand why different chronic stress paradigms have differing effects on dopamine neurons, it is essential to conceptualize chronic stress not as a single experience, but as a sequence of smaller building blocks of acute stress, threat of stress, acute relief [40], and learning about the utility or futility of actions being taken [92] (Figure 2a). The state of the VTA during and after stress will reflect the interaction of these blocks of experience and the Hebbian and homeostatic plasticity induced as they accumulate. Different chronic stressors lead to varied results partly because they represent different experiences that pose distinct demands on the animal for survival.

Figure 2. Heterogeneous effects of repeated stress.

Figure 2.

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a) Rather than being a uniform process, repeated stress exposure can vary in its features—stressors may be predictable or unpredictable, and possibly interspersed with periods of threat or recovery. Responses to each event are shaped by multiple factors, including the nature of the aversive signals, physical demands, learning processes, emotional reactivity, and environmental context, which may be different with each exposure. b) Each successive stressor can alter both the intensity of the physiological response and the trajectory of recovery, potentially leading to a progressive shift in baseline functioning. The schematic illustrates two possible outcomes: lighter lines represent sensitization, where responses intensify over time, while darker lines indicate habituation or response blunting with repeated exposure. c) While individual stressors can directly influence synaptic strength, interactions between inputs can also give rise to distinct forms of plasticity and metaplasticity. This panel illustrates how the same input (colored line) may undergo different synaptic outcomes depending on prior stressor exposure.

The VTA is an integrative hub, receiving information about the internal state of the animal and external environment from a wide range of inputs. For each session of acute stress, the VTA will not receive a unified signal indicating “stress” but instead a barrage of multifaceted information. Some of these signals will be consistent across modalities of stress. For example, the VTA is responsive to Hypothalamic-pituitary-adrenal (HPA) axis hormones like corticotropin-releasing factor [93], signals of arousal such as norepinephrine [94] and acetylcholine [95–97], and to peptides released by aversive experiences such as dynorphin [56,98]. However, there are a number of inputs that may vary significantly across stressors. Proprioceptive information [22,99], interoceptive signals relayed from the vagal nerve [100], valence signals [10,101], and indicators of metabolic state [20,102] are processed by VTA neurons and may vary between stressors. Chronic stress paradigms also include periods in which the animal is under threat but not actively in physical danger, and of relief, where no threat or active stress is present. These are periods of continuing adaptation within the brain. In this light, it is unsurprising that a chronic stressor with short bursts of physical activity followed by prolonged presence of a threat, such as CSDS, and a chronic stressor consisting of multiple periods of unpredictable periods of contextual shifts, homeostatic challenges, and social changes would have different outcomes: they are different experiences exerting distinct challenges on the animal’s current and future ability to maintain homeostasis (Figure 2b).

Conceptualizing chronic stress as a multi-dimensional experience highlights a critical role for incoming projections into the VTA from distal brain regions. A given stressor will activate a collection of degenerate and distinct inputs. Stress modulates the synaptic strength of many of these inputs. Much of current knowledge of this stems from studies focusing on plasticity of single inputs. For example, in mice, social stress-induced strengthening of lateral hypothalamic glutamatergic inputs to the VTA promotes overeating of palatable food [103], CUS-induced strengthening of lateral habenula inputs promotes passive responses to acute stressors [104], and chronic social defeat stress increases the excitability of laterodorsal tegmental cholinergic inputs which promote social avoidance and decreased sucrose preference [79]. However, plasticity and metaplasticity that arise from interactions between inputs remain largely unexplored. Cooperative and permissive forms of plasticity through which inputs can jointly induce alterations or regulate the plastic potential of each other provide a wide range of possibilities for nuanced modulation of VTA output and storage of information. This constellation of stress-induced plasticity processes may reorganize the inputs of the VTA, and prime VTA neurons for shifted behavioral and physiological responses to future experience. This could contribute to a wide range of behavioral adjustments following stress, from avoidance of stress-related cues, changes in food consumption and activity levels following exertion, or shifts in exploit-explore tradeoffs during exploration. Stress-induced plasticity at some inputs may also prime the circuit for more robust responses to future stressors. The relative balance of stress-induced changes may change over time; for example, a change in inputs resulting from increased energy demand during physically challenging stressors may last as long as it takes to refill energy stores, while plasticity associated with contextual cues might linger for a much longer time. In this way, chronic stressors can exert multiphasic effects on physiological signatures in the VTA (Figure 2c).

Stress signaling as a convergence of multiple inputs onto the VTA also highlights a key role for VTA GABA neurons. Numerous projections into the VTA, such as those from the BNST [49] and LH [105], have stronger connections onto GABA neurons relative to dopaminergic neurons. This preferential input onto GABA neurons positions them as the primary receiver of most external input from outside of the VTA, making them major sites of integration for multiple streams of information which is then transmitted via inhibitory connections to dopaminergic neurons. This is seen in a recent study in mice in which deep brain stimulation of the NAc led to reversal of CUS-induced behavioral deficits through VTA GABA neuron-mediated disinhibition of dopaminergic neurons [106].

Individual differences in stress responses are a powerful tool for understanding how different factors affect behavioral outcomes. For most stressors, the vigor of behavioral responses and adoption of behavioral strategies can vary considerably between animals. This will lead to qualitative and quantitative variability of activity of inputs related to motion and energy expenditure, differing patterns of stress and relief, or controllability of the stressor that can drive distinct forms of plasticity between individuals. Using behavioral analyses during stress as well as in combination with techniques for measuring peripheral physiological responses such as heart rate, blood pressure, and blood glucose to monitor these responses during chronic stress can lead to correlative studies that can illustrate the relationship between these factors and post-stress sequelae and point towards targets for causal studies.

Different circuit adaptations, same behavior

One of the vexing questions in the context of stress responses and the VTA is how opposing adaptations to the dopaminergic system can lead to similar effects on dopamine-dependent behaviors. One potential factor is that neuromodulatory actions are dependent on both the dynamics of the neuromodulator itself and the ongoing state of the receiving circuit.

Absolute measures of dopaminergic activity must therefore be considered within the context of a remodeled circuit. Firing of action potentials from dopaminergic cell bodies is only one of several points where dopaminergic function can be regulated [107], as numerous neuromodulators can regulate terminal release of dopamine [108] and cholinergic innervation of dopaminergic axons can directly drive action potentials [109]. It is thus possible that divergent firing rates in response to different chronic stress paradigms could be complemented by changes elsewhere on dopaminergic neurons that alter ultimate release of dopamine. Alterations in the state of the dopaminoceptive circuit could also play a role, as receptor level and function, excitability and synaptic input to postsynaptic cells, and balance of activity between different types of cells, can all change the circuit-level effects of dopamine release. By changing these elements, the “optimal” level of dopamine release for shaping reward-related behavior might be different. Understanding how chronic stress affects somatic firing of dopamine neurons is a critical step to understanding the function of this system, but just one point of several that can determine ultimate output.

Many studies of dopaminergic function following chronic stress have relied on “snapshot” measurements from a single point in time. These measurements are an outstanding starting point and are essential for understanding mechanistic changes following chronic stress, yet they provide limited information about the dynamics of the system over time. One can imagine that a reduction in excitability associated with reduced basal firing (as occurs in CUS) and an elevated basal firing rate (as occurs in CSDS) might both lead to anhedonia by reducing the dynamic range of the system. In both cases, the problem is not the absolute level of dopamine, but rather the inability to mount a robust increase in dopamine levels relative to baseline in response to appropriate stimuli. Emerging technologies such as calcium and biosensor imaging in behaving animals have reduced barriers to longitudinal studies, and experiments measuring circuit activity during behavioral tasks will be particularly valuable.

Finally, we must consider the possibility that given the imprecise nature of behavioral tests being used, different chronic stress paradigms do not in fact induce similar behavioral outcomes. For instance, while social interaction and sucrose preference tests are excellent tools for screening gross deficits in sociability and reward consumption, respectively, both tests can arrive at similar outcomes through distinct behavioral mechanisms. Analysis of the microstructure of sucrose consumption during a sucrose preference test showed that a decrease in sucrose preference could be explained by both a decrease in learning rate and by anhedonia, and that different stressors decreased sucrose preference through distinct mechanisms [110]. Sucrose preference can be supported independently of dopamine [111], raising the possibility that some components of this behavioral assay might arise from circuits other than the VTA. Decreases in social interaction are frequently interpreted as anhedonia, but post-defeat decreases in social interaction may be equally driven by learning-based avoidance of an aggressor [112,113]. Thus, what appear to be identical behavioral changes may reflect distinct behavioral phenomena, with differing underlying mechanisms. This highlights the need to integrate acute and chronic stress studies with complex operant and naturalistic behavioral tasks that can more precisely capture nuanced changes in dopamine-dependent behaviors and how they evolve over time.

Concluding remarks

In this review, we have highlighted the effects of stress on VTA function, offering potential explanations for contradictions in the literature. The considerations discussed here reveal many exciting avenues for future work (see Outstanding questions), including longitudinal studies to capture the progression of plasticity during and after stress, a focus on interactive and cumulative effects of activation of multiple inputs during multi-dimensional stress experiences, and better understanding of the organization and roles of non-dopaminergic neurons in the VTA. Integrating findings from these lines of research into a more comprehensive picture will further our understanding of the biology of stress.

Outstanding Questions.

  • How do different stressors shape unique neuronal adaptations in the VTA while producing similar behaviors?

  • How do VTA GABA and glutamate neurons contribute to stress-induced adaptations in both dopamine dependent and independent ways?

  • What role does the VTA play in stress-induced behavior changes in complex behaviors such as learning, decision making, and motivation? How can current behavioral assays be optimized to measure more granular features of these behaviors?

  • What mechanisms translate repeated stress into long-term changes in VTA function?

  • How do specific inputs carrying distinct modalities of information affect function of neurons in the VTA and how are these signals integrated?

  • How do VTA neuronal signaling and behavioral choices during stress contribute to post-stress behavioral and neuronal adaptations?

  • What processes underlie recovery from chronic stress, and can they be used to promote resilience and adaptation?

  • How can current knowledge of heterogeneous mechanisms underlying stress responses in the rodent VTA be best applied to an (also heterogeneous) population of humans suffering from stress-induced neuropsychiatric disorders?

In addition to the work covered in this review, there are several additional factors that will be important to integrate into our understanding of the effects of stress on the VTA. The vast majority of studies covered on this topic have used male rodents, as exclusive use of males was the norm in the field until recently. There is ample reason to believe that the VTA may respond to stress in a sexually divergent fashion [114], and further studies focused on female animals will be critical to gain perspective on the full range of behavioral and physiological responses to stress. While this review focused on the effects of stress in adults, there is a rich literature examining developmental effects of stress on the VTA [115]. It will be important to understand how reorganization of the VTA by developmental stressors can set the stage for susceptibility to subsequent insults.

Finally, while this review focused on rodent studies, the question of how to best translate these findings to humans is a vital one. Future work in humans must better account for the roles of distinct VTA subpopulations across both healthy and pathological states. Promising strategies include high-field fMRI to resolve VTA signals and connectivity, MR spectroscopy and PET to assess GABA and glutamate signaling, and postmortem spatial transcriptomics to map subregion- and cell-type–specific profiles [116]. Another avenue involves developing deep brain stimulation protocols that mimic VTA synaptic plasticity or electrophysiological patterns [117], potentially translating insights—such as the role of VTA GABA neuron activity in disrupting reward seeking—into clinical interventions. Perhaps the most challenging aspect of translating the findings from rodent studies is recognition that the heterogeneity seen in preclinical models of stress is likely to be present in humans as well, with the added wrinkle that humans live more complex lives than a laboratory rodent. Understanding sources of this heterogeneity-in humans and rodents-will be critical to designing efficient pipelines for identifying and testing potential interventions. Approaching translation with a view that there are many paths to similar-looking outcomes makes our task more challenging, but also presents many more opportunities for understanding the richness of brain and behavior.

Highlights.

  • Acute and chronic stressors of different types trigger a range of heterogeneous adaptations within the VTA.

  • Neuronal adaptations resulting from a variety of emotional, physical, and temporal features of stress may contribute to heterogeneity in stress responses.

  • VTA neurons receive a range of inputs encoding distinct features of stress. Understanding the integration of these inputs and the interactions between them is key to defining the role of the VTA in stress.

  • Emerging technologies enabling longitudinal monitoring of neuronal function and integration of complex behavior with stress paradigms provide exciting opportunities for advancing our knowledge of complex interactions of stress and the dopaminergic system

Acknowledgements:

This work was supported by R01MH122712 (AMP), R01MH124998 (AZH), and 2024 NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation (US).

Footnotes

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Declaration of interests:

Authors declare no competing interests.

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