Ventral tegmental area GABA neurons mediate stress-induced blunted reward-seeking in mice

Lowes, Daniel C.; Chamberlin, Linda A.; Kretsge, Lisa N.; Holt, Emma S; Abbas, Atheir I.; Park, Alan J.; Yusufova, Lyubov; Bretton, Zachary H.; Firdous, Ayesha; Enikolopov, Armen G.; Gordon, Joshua A.; Harris, Alexander Z.

doi:10.1038/s41467-021-23906-2

Cited by 49 publications

(35 citation statements)

References 58 publications

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“…Mann et al reported that the GABA level in CSF was lower in MDD patients compared with healthy controls, and the lower level was correlated with increasing severity of anxiety in the patients [112]. GABA neurons are broadly present in the brain, and participate in many functions, including anxiety, motivation, and the reward system [113][114][115], as well as playing an important role in ameliorating MDD symptoms [116].…”

Section: Dysregulation Of Monoamines and Gamma-aminobutyric Acidmentioning

confidence: 99%

How Microbes Affect Depression: Underlying Mechanisms via the Gut–Brain Axis and the Modulating Role of Probiotics

Suda

Matsuda

2022

IJMS

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Accumulating evidence suggests that the gut microbiome influences the brain functions and psychological state of its host via the gut–brain axis, and gut dysbiosis has been linked to several mental illnesses, including major depressive disorder (MDD). Animal experiments have shown that a depletion of the gut microbiota leads to behavioral changes, and is associated with pathological changes, including abnormal stress response and impaired adult neurogenesis. Short-chain fatty acids such as butyrate are known to contribute to the up-regulation of brain-derived neurotrophic factor (BDNF), and gut dysbiosis causes decreased levels of BDNF, which could affect neuronal development and synaptic plasticity. Increased gut permeability causes an influx of gut microbial components such as lipopolysaccharides, and the resultant systemic inflammation may lead to neuroinflammation in the central nervous system. In light of the fact that gut microbial factors contribute to the initiation and exacerbation of depressive symptoms, this review summarizes the current understanding of the molecular mechanisms involved in MDD onset, and discusses the therapeutic potential of probiotics, including butyrate-producing bacteria, which can mediate the microbiota–gut–brain axis.

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Section: Dysregulation Of Monoamines and Gamma-aminobutyric Acidmentioning

confidence: 99%

How Microbes Affect Depression: Underlying Mechanisms via the Gut–Brain Axis and the Modulating Role of Probiotics

Suda

Matsuda

2022

IJMS

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“…To illustrate this approach, recent studies using intracortical recordings have observed that low-frequency (2-7 Hz) oscillations emerge during stressful and anxiety-like conditions in many limbic areas such as the ventral tegmental area (VTA), nucleus accumbens (NAc), amygdala and prelimbic cortex (Kumar et al, 2014;Karalis et al, 2016;Lowes et al, 2021). These brain areas play crucial roles in mediating such disparate consequences of stress as decreased reward seeking and fear-induced freezing.…”

Section: Rhythms As a Window To Understand The Neuronal Circuits Unde...mentioning

confidence: 99%

“…These brain areas play crucial roles in mediating such disparate consequences of stress as decreased reward seeking and fear-induced freezing. Investigating the circuit basis of these rhythms in different behavioral contexts reveals that the low-frequency rhythm that accompanies stress-induced deficits in reward seeking reflects VTA to NAc circuit activity (Lowes et al, 2021). By contrast, freezing behavior co-occurs with a synchronization of prelimbic cortex and amygdala (Lesting et al, 2011;Likhtik et al, 2014;Stujenske et al, 2014;Karalis et al, 2016).…”

Section: Rhythms As a Window To Understand The Neuronal Circuits Unde...mentioning

confidence: 99%

“…For example, while rodent hippocampal theta rhythms represent one of the most wellunderstood oscillations (Hasselmo, 2005), human hippocampal "theta" rhythms may actually fall in the delta range (Watrous et al, 2013;Jacobs, 2014). In mice, we recently found that the same stressor induced nucleus accumbens oscillations in the delta or the theta range depending on the strain, suggesting genetic differences play a role in frequency boundaries (Lowes et al, 2021). Similarly, some individuals, have beta oscillations that function the way alpha rhythms do in other individuals (Haegens et al, 2014).…”

Section: Introduction Historymentioning

confidence: 99%

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Breaking Down a Rhythm: Dissecting the Mechanisms Underlying Task-Related Neural Oscillations

Ibarra-Lecue

Haegens

Harris

2022

Front. Neural Circuits

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A century worth of research has linked multiple cognitive, perceptual and behavioral states to various brain oscillations. However, the mechanistic roles and circuit underpinnings of these oscillations remain an area of active study. In this review, we argue that the advent of optogenetic and related systems neuroscience techniques has shifted the field from correlational to causal observations regarding the role of oscillations in brain function. As a result, studying brain rhythms associated with behavior can provide insight at different levels, such as decoding task-relevant information, mapping relevant circuits or determining key proteins involved in rhythmicity. We summarize recent advances in this field, highlighting the methods that are being used for this purpose, and discussing their relative strengths and limitations. We conclude with promising future approaches that will help unravel the functional role of brain rhythms in orchestrating the repertoire of complex behavior.

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“…Therefore, nicotine directly activates DA neurons and indirectly activates glutamate and GABA neurons, enhancing DA release within the NAcShell [10][11][12]. Previous studies also suggest that GABAergic neurons regulate DA neurons [13][14][15]. A recent study shows that the inter-play between DAergic and GABAergic transmission presents novel relevant mechanisms in reinforcing addiction to alcohol and other addictive drugs [16].…”

Section: Introductionmentioning

confidence: 99%

Investigating the Influence of GABA Neurons on Dopamine Neurons in the Ventral Tegmental Area Using Optogenetic Techniques

Ohta

Murakami

Kawahara

et al. 2022

IJMS

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Dopamine (DA) is the key regulator of reward behavior. The DA neurons in the ventral tegmental area (VTA) and their projection areas, which include the prefrontal cortex (PFC), nucleus accumbens (NAc), and amygdala, play a primary role in the process of reward-driven behavior induced by the drugs of addiction, including nicotine and alcohol. In our previous study, we developed a novel platform consisting of micro-LED array devices to stimulate a large area of the brain of rats and monkeys with photo-stimulation and a microdialysis probe to estimate the DA release in the PFC. Our results suggested that the platform was able to detect the increased level of dopamine in the PFC in response to the photo-stimulation of both the PFC and VTA. In this study, we used this platform to photo-stimulate the VTA neurons in both ChrimsonR-expressing (non-specific) wild and dopamine transporter (DAT)-Cre (dopamine specific) mice, and measured the dopamine release in the nucleus accumbens shell (NAcShell). We measured the DA release in the NAcShell in response to optogenetic stimulation of the VTA neurons and investigated the effect of GABAergic neurons on dopaminergic neurons by histochemical studies. Comparing the photo-stimulation frequency of 2 Hz with that of 20 Hz, the change in DA concentration at the NAcShell was greater at 20 Hz in both cases. When ChrimsonR was expressed specifically for DA, the release of DA at the NAcShell increased in response to photo-stimulation of the VTA. In contrast, when ChrimsonR was expressed non-specifically, the amount of DA released was almost unchanged upon photo-stimulation. However, for nonspecifically expressed ChrimsonR, intraperitoneal injection of bicuculline, a competitive antagonist at the GABA-binding site of the GABAA receptor, also significantly increased the release of DA at the NAcShell in response to photo-stimulation of the VTA. The results of immunochemical staining confirm that GABAergic neurons in the VTA suppress DA activation, and also indicate that alterations in GABAergic neurons may have serious downstream effects on DA activity, NAcShell release, and neural adaptation of the VTA. This study also confirms that optogenetics technology is crucial to study the relationship between the mesolimbic dopaminergic and GABAergic neurons in a neural-specific manner.

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Ventral tegmental area GABA neurons mediate stress-induced blunted reward-seeking in mice

Cited by 49 publications

References 58 publications

How Microbes Affect Depression: Underlying Mechanisms via the Gut–Brain Axis and the Modulating Role of Probiotics

How Microbes Affect Depression: Underlying Mechanisms via the Gut–Brain Axis and the Modulating Role of Probiotics

Breaking Down a Rhythm: Dissecting the Mechanisms Underlying Task-Related Neural Oscillations

Investigating the Influence of GABA Neurons on Dopamine Neurons in the Ventral Tegmental Area Using Optogenetic Techniques

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