Activation of VTA GABA Neurons Disrupts Reward Seeking by Altering Temporal Processing

10.1101/2020.08.18.256073 ◽

2020 ◽

Author(s):

Andrea K. Shields ◽

Mauricio Suarez ◽

Ken T. Wakabayashi ◽

Caroline E. Bass

Keyword(s):

Temporal Processing ◽

Interval Timing ◽

Gabaergic Neurons ◽

Male Rats ◽

Session Length ◽

Gaba Neurons ◽

Reward Seeking ◽

Perception Of Time ◽

Cue Processing

AbstractThe role of ventral tegmental area (VTA) dopamine in reward, cue processing, and interval timing is well characterized. Using a combinatorial viral approach to target activating DREADDs (Designer Receptors Exclusively Activated by Designer Drugs, hM3D) to GABAergic neurons in the VTA of male rats, we previously showed that activation disrupts responding to reward-predictive cues. Here we explored how VTA GABA neurons influence the perception of time in two fixed interval (FI) tasks, one where the reward or interval is not paired with predictive cues (Non-Cued FI), and another where the start of the FI is signaled by a constant tone that continues until the rewarded response is emitted (Cued FI). Under vehicle conditions in both tasks, responding was characterized by “scalloping” over the 30s FI, in which responding increased towards the end of the FI. However, when VTA GABA neurons were activated in the Non-Cued FI, the time between the end of the 30s interval and when the rats made a reinforced response increased. Additionally, post-reinforcement pauses and overall session length increased. In the Cued FI task, VTA GABA activation produced erratic responding, with a decrease in earned rewards. Thus, while both tasks were disrupted by VTA GABA activation, responding that is constrained by a cue was more sensitive to this manipulation, possibly due to convergent effects on timing and cue processing. Together these results demonstrate that VTA GABA activity disrupts the perception of interval timing, particularly when the timing is set by cues.

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Ventral tegmental area GABA neurons mediate stress-induced anhedonia

10.1101/2020.05.28.121905 ◽

2020 ◽

Author(s):

Daniel C. Lowes ◽

Linda A. Chamberlin ◽

Lisa N. Kretsge ◽

Emma S. Holt ◽

Atheir I. Abbas ◽

...

Keyword(s):

Ventral Tegmental Area ◽

Low Frequency ◽

Potential Mechanism ◽

Gaba Neurons ◽

Reward Seeking ◽

Seeking Behavior ◽

Stressful Experiences ◽

Ventral Tegmental ◽

Necessary And Sufficient ◽

Depressive Episodes

AbstractStressful experiences frequently precede depressive episodes1. Depression results in anhedonia, or disrupted reward-seeking, in most patients2. In humans3,4 and rodents5,6, stress can disrupt reward-seeking, providing a potential mechanism by which stress can precipitate depression7-9. Yet despite decades investigating how stress modulates dopamine neuron transmission between the ventral tegmental area (VTA) and nucleus accumbens (NAc), the underpinnings of the stress-anhedonia transition remain elusive10-13. Here we show that during restraint stress, VTA GABA neurons drive low frequency NAc LFP oscillations, rhythmically modulating NAc firing rates. The strength of these stress-induced NAc oscillations predict the degree of impaired reward-seeking upon release from restraint. Inhibiting VTA GABA neurons disrupts stress-induced NAc oscillations and reverses the effect of stress on reward-seeking. By contrast, mimicking these oscillations with rhythmic VTA GABA stimulation in the absence of stress blunts subsequent reward-seeking. These experiments demonstrate that VTA GABA inputs to the NAc are both necessary and sufficient for stress-induced decreases in reward seeking behavior, elucidating a key circuit-level mechanism underlying stress-induced anhedonia.

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

Nature Communications ◽

10.1038/s41467-021-23906-2 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Daniel C. Lowes ◽

Linda A. Chamberlin ◽

Lisa N. Kretsge ◽

Emma S. Holt ◽

Atheir I. Abbas ◽

...

Keyword(s):

Ventral Tegmental Area ◽

Neural Activity ◽

Neural Encoding ◽

Brain Areas ◽

Gaba Neurons ◽

Reward Seeking ◽

Core Symptom ◽

Stressful Experiences ◽

Ventral Tegmental ◽

Gabaergic Activity

AbstractDecreased pleasure-seeking (anhedonia) forms a core symptom of depression. Stressful experiences precipitate depression and disrupt reward-seeking, but it remains unclear how stress causes anhedonia. We recorded simultaneous neural activity across limbic brain areas as mice underwent stress and discovered a stress-induced 4 Hz oscillation in the nucleus accumbens (NAc) that predicts the degree of subsequent blunted reward-seeking. Surprisingly, while previous studies on blunted reward-seeking focused on dopamine (DA) transmission from the ventral tegmental area (VTA) to the NAc, we found that VTA GABA, but not DA, neurons mediate stress-induced blunted reward-seeking. Inhibiting VTA GABA neurons disrupts stress-induced NAc oscillations and rescues reward-seeking. By contrast, mimicking this signature of stress by stimulating NAc-projecting VTA GABA neurons at 4 Hz reproduces both oscillations and blunted reward-seeking. Finally, we find that stress disrupts VTA GABA, but not DA, neural encoding of reward anticipation. Thus, stress elicits VTA-NAc GABAergic activity that induces VTA GABA mediated blunted reward-seeking.

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Chemogenetic activation of mesoaccumbal Gamma-Aminobutyric Acid projections selectively tunes responses to predictive cues when reward value is abruptly decreased

10.1101/2020.03.04.977371 ◽

2020 ◽

Cited By ~ 1

Author(s):

Ken T. Wakabayashi ◽

Malte Feja ◽

Martin P.K. Leigh ◽

Ajay N. Baindur ◽

Mauricio Suarez ◽

...

Keyword(s):

Aminobutyric Acid ◽

Male Rats ◽

Gamma Aminobutyric Acid ◽

Inhibitory Circuits ◽

Gaba Neurons ◽

Reward Seeking ◽

Reward Value ◽

Seeking Behavior ◽

Adaptive Responding ◽

Viral Targeting

ABSTRACTBackgroundMesolimbic circuits regulate the attribution of motivational significance to incentive cues that predict reward, yet this network also plays a key role in adapting reward-seeking behavior when the contingencies linked to a cue unexpectedly change. Here we asked whether mesoaccumbal gamma-aminobutyric acid (GABA) projections enhance adaptive responding to incentive cues of abruptly altered reward value, and whether these effects were distinct from global activation of all ventral tegmental area (VTA) GABA circuits.MethodsWe used a viral targeting system to chemogenetically activate mesoaccumbal GABA projections in male rats during a novel cue-dependent operant Value Shifting (VS) task, in which the volume of a sucrose reward associated with a predictive cue is suddenly altered, from the beginning and throughout the session. We compared the results with global activation of VTA GABA neurons, which will activate local inhibitory circuits and long loop projections.ResultsWe found that activation of mesoaccumbal GABA projections decreases responding to incentive cues associated with smaller-than-expected rewards. This tuning of behavioral responses was specific to cues associated with smaller-than-expected rewards, but did not impact measures related to consuming the reward. In marked contrast, activating all VTA(GABA) neurons resulted in a uniform decrease in responding to incentive cues irrespective of changes in the size of the reward.ConclusionsTargeted activation of mesoaccumbal GABA neurons facilitate adaptation in reward-seeking behaviors. This suggests that these projections may play a very specific role in associative learning processes.

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Hope, exploration, and equilibrated action schemes

Behavioral and Brain Sciences ◽

10.1017/s0140525x18001863 ◽

2019 ◽

Vol 42 ◽

Cited By ~ 2

Author(s):

Davood G. Gozli ◽

Ci Jun Gao

Keyword(s):

Single Type ◽

Reward Seeking ◽

Stable Scheme

AbstractThe concepts want, hope, and exploration cannot be organized in relation to a single type of motive (e.g., motive for food). They require, in addition, the motive for acquiring and maintaining a stable scheme that enables reward-directed activity. Facing unpredictability, the animal has to seek not only reward, but also a new equilibrated state within which reward seeking is possible.

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