2022 Theses Doctoral

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

Lowes, Daniel Christopher

Decreased reward-seeking, often called anhedonia, forms a core symptom of depression. Often, decreased reward-seeking appears as impaired reward anticipation. Stressful experiences precipitate depression and disrupt reward-seeking, but it remains unclear how stress causes anhedonia. To determine how stress alters neural communication, 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) local field potential (LFP) that predicts the degree of subsequent blunted reward-seeking. This 4 Hz oscillation exhibited strong coherence between the ventral tegmental area (VTA) and the NAc.

Through pharmacological inhibition of the VTA, we found that VTA neural activity is necessary for the generation of the 4 Hz oscillation, and extracellular recordings of multi-unit activity in the VTA reveal that VTA neural activity leads the phase of the 4 Hz NAc oscillation. We used transgenic mouse lines to selectively express the inhibitory opsin Archaerhodopsin in dopamine (DA), GABA, and glutamate neurons in the VTA. We combined cell type specific optogenetic inhibition with extracellular single-unit recordings in the VTA and LFP recordings in the NAc to identify the phase-locking of specific cell type spiking with the NAc4 Hz oscillation, as well as to identify the extent to which VTA populations contribute to the generation of the 4 Hz NAc oscillation.

We found that VTA GABA neuron firing leads the phase of the 4 Hz NAc oscillation, and that VTA GABA activity is necessary for the generation of the 4 Hz NAc oscillation. This result led us to determine whether rhythmic VTA GABA activity contributes to stress-induced anhedonia. Surprisingly, while previous studies on blunted reward-seeking focused on DA transmission from the VTA to the NAc, we found that VTA GABA neurons mediate stress-induced blunted reward-seeking. Inhibiting VTA GABA neurons during stress 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 in the absence of stress reproduces both oscillations and blunted reward-seeking. Finally, we found that stress disrupts VTA GABA, but not VTA DA, neural encoding of reward anticipation. Thus, stress elicits rhythmic VTA-NAc GABAergic activity that induces VTA GABA mediated blunted reward-seeking.